1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto

ABSTRACT

The present invention relates to certain trisubstituted aryl and heteroaryl derivatives of Formula (I) that are modulators of metabolism. 
     
       
         
         
             
             
         
       
     
     Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such as, diabetes and obesity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/602,775, filed onNov. 21, 2006, which is a continuation of U.S. Ser. No. 10/888,747,filed on Jul. 9, 2004, now U.S. Pat. No. 7,470,699, which in turn claimsthe benefit of U.S. Ser. No. 60/486,728, filed on Jul. 11, 2003, andU.S. Ser. No. 60/487,370, filed on Jul. 14, 2003, the disclosures ofeach of which are herein incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to certain trisubstituted aryl andheteroaryl derivatives that are modulators of glucose metabolism.Accordingly, compounds of the present invention are useful in theprophylaxis or treatment of metabolic disorders and complicationsthereof, such as, diabetes and obesity.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious disease afflicting over 100 millionpeople worldwide. In the United States, there are more than 12 milliondiabetics, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorderscharacterized by abnormal glucose homeostasis resulting in elevatedblood sugar. There are many types of diabetes, but the two most commonare Type I (also referred to as insulin-dependent diabetes mellitus orIDDM) and Type II (also referred to as non-insulin-dependent diabetesmellitus or NIDDM). The etiology of the different types of diabetes isnot the same; however, everyone with diabetes has two things in common:overproduction of glucose by the liver and little or no ability to moveglucose out of the blood into the cells where it becomes the body'sprimary fuel.

People who do not have diabetes rely on insulin, a hormone made in thepancreas, to move glucose from the blood into the cells of the body.However, people who have diabetes either don't produce insulin or can'tefficiently use the insulin they produce; therefore, they can't moveglucose into their cells. Glucose accumulates in the blood creating acondition called hyperglycemia, and over time, can cause serious healthproblems.

Diabetes is a syndrome with interrelated metabolic, vascular, andneuropathic components. The metabolic syndrome, generally characterizedby hyperglycemia, comprises alterations in carbohydrate, fat and proteinmetabolism caused by absent or markedly reduced insulin secretion and/orineffective insulin action. The vascular syndrome consists ofabnormalities in the blood vessels leading to cardiovascular, retinaland renal complications. Abnormalities in the peripheral and autonomicnervous systems are also part of the diabetic syndrome.

People with IDDM, which accounts for about 5% to 10% of those who havediabetes, don't produce insulin and therefore must inject insulin tokeep their blood glucose levels normal. IDDM is characterized by low orundetectable levels of endogenous insulin production caused bydestruction of the insulin-producing β cells of the pancreas, thecharacteristic that most readily distinguishes IDDM from NIDDM. IDDM,once termed juvenile-onset diabetes, strikes young and older adultsalike.

Approximately 90 to 95% of people with diabetes have Type II (or NIDDM).NIDDM subjects produce insulin, but the cells in their bodies areinsulin resistant: the cells don't respond properly to the hormone, soglucose accumulates in their blood. NIDDM is characterized by a relativedisparity between endogenous insulin production and insulinrequirements, leading to elevated blood glucose levels. In contrast toIDDM, there is always some endogenous insulin production in NIDDM; manyNIDDM patients have normal or even elevated blood insulin levels, whileother NIDDM patients have inadequate insulin production (Rotwein, R. etal. N. Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed withNIDDM are age 30 or older, and half of all new cases are age 55 andolder. Compared with whites and Asians, NIDDM is more common amongNative Americans, African-Americans, Latinos, and Hispanics. Inaddition, the onset can be insidious or even clinically inapparent,making diagnosis difficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many havesuggested that primary insulin resistance of the peripheral tissues isthe initial event. Genetic epidemiological studies have supported thisview. Similarly, insulin secretion abnormalities have been argued as theprimary defect in NIDDM. It is likely that both phenomena are importantcontributors to the disease process (Rimoin, D. L., et. al. Emery andRimoin's Principles and Practice of Medical Genetics 3^(rd) Ed.1:1401-1402 (1996)).

Many people with NIDDM have sedentery lifestyles and are obese; theyweigh approximately 20% more than the recommended weight for theirheight and build. Furthermore, obesity is characterized byhyperinsulinemia and insulin resistance, a feature shared with NIDDM,hypertension and atherosclerosis.

Obesity and diabetes are among the most common human health problems inindustrialized societies. In industrialized countries a third of thepopulation is at least 20% overweight. In the United States, thepercentage of obese people has increased from 25% at the end of the1970s, to 33% at the beginning the 1990s. Obesity is one of the mostimportant risk factors for NIDDM. Definitions of obesity differ, but ingeneral, a subject weighing at least 20% more than the recommendedweight for his/her height and build is considered obese. The risk ofdeveloping NIDDM is tripled in subjects 30% overweight, andthree-quarters with NIDDM are overweight.

Obesity, which is the result of an imbalance between caloric intake andenergy expenditure, is highly correlated with insulin resistance anddiabetes in experimental animals and human. However, the molecularmechanisms that are involved in obesity-diabetes syndromes are notclear. During early development of obesity, increase insulin secretionbalances insulin resistance and protects patients from hyperglycemia (LeStunff, et al. Diabetes 43, 696-702 (1989)). However, after severaldecades, β cell function deteriorates and non-insulin-dependent diabetesdevelops in about 20% of the obese population (Pederson, P. Diab. Metab.Rev. 5, 505-509 (1989)) and (Brancati, F. L., et al., Arch. Intern. Med.159, 957-963 (1999)). Given its high prevalence in modern societies,obesity has thus become the leading risk factor for NIDDM (Hill, J. O.,et al., Science 280, 1371-1374 (1998)). However, the factors whichpredispose a fraction of patients to alteration of insulin secretion inresponse to fat accumulation remain unknown.

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m² (see TABLE below). There are problems with this definitionin that it does not take into account the proportion of body mass thatis muscle in relation to fat (adipose tissue). To account for this,obesity can also be defined on the basis of body fat content: greaterthan 25% and 30% in males and females, respectively.

Classification of Weight by Body Mass Index (BMI)

BMI CLASSIFICATION <18.5 Underweight 18.5-24.9 Normal 25.0-29.9Overweight 30.0-34.9 Obesity (Class I) 35.0-39.9 Obesity (Class II) >40Extreme Obesity (Class III)

As the BMI increases there is an increased risk of death from a varietyof causes that is independent of other risk factors. The most commondiseases with obesity are cardiovascular disease (particularlyhypertension), diabetes (obesity aggravates the development ofdiabetes), gall bladder disease (particularly cancer) and diseases ofreproduction. Research has shown that even a modest reduction in bodyweight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (XENICAL™)and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorptiondirectly and tends to produce a high incidence of unpleasant (thoughrelatively harmless) side-effects such as diarrhea. Sibutramine (a mixed5-HT/noradrenaline reuptake inhibitor) can increase blood pressure andheart rate in some patients. The serotonin releaser/reuptake inhibitorsfenfluramine (Pondimin™) and dexfenfluramine (Redux™) have been reportedto decrease food intake and body weight over a prolonged period (greaterthan 6 months). However, both products were withdrawn after reports ofpreliminary evidence of heart valve abnormalities associated with theiruse. Accordingly, there is a need for the development of a saferanti-obesity agent.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplication induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents by 35%. The incidence of coronary diseases is doubledin subjects less than 50 years of age who are 30% overweight. Thediabetes patient faces a 30% reduced lifespan. After age 45, people withdiabetes are about three times more likely than people without diabetesto have significant heart disease and up to five times more likely tohave a stroke. These findings emphasize the inter-relations betweenrisks factors for NIDDM and coronary heart disease and the potentialvalue of an integrated approach to the prevention of these conditionsbased on the prevention of these conditions based on the prevention ofobesity (Perry, I. J., et al., BMJ 310, 560-564 (1995)).

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

SUMMARY OF THE INVENTION

The present invention is drawn to compounds which bind to and modulatethe activity of a GPCR, referred to herein as RUP3, and uses thereof.The term RUP3 as used herein includes the human sequences found inGeneBank accession numbers XM_(—)066873 and AY288416, andnaturally-occurring allelic variants, mammalian orthologs, andrecombinant mutants thereof. A preferred human RUP3 for use in screeningand testing of the compounds of the invention is provided in thenucleotide sequence of Seq. ID.No:1 and the corresponding amino acidsequence in Seq. ID.No:2.

One aspect of the present invention encompasses trisubstituted aryl andheteroaryl derivatives as shown in Formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate, or N-oxidethereof;

wherein:

A and B are each independently C₁₋₃ alkylene optionally substituted with1 to 4 substituents selected from the group consisting of C₁₋₃ alkyl,C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen;

D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂;

E is N, C or CR₄;

is a single bond when E is N or CR₄, or a double bond when E is C;

V₁ is selected from the group consisting of C₁₋₃ alkylene, ethynyleneand C₁₋₂ heteroalkylene optionally substituted with 1 to 4 substituentsselected from the group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy,cyano, C₁₋₃ haloalkyl and halogen; or V₁ is a bond;

V₂ is C₃₋₆ cycloalkylene or C₁₋₃ alkylene wherein each are optionallysubstituted with 1 to 4 substituents selected from the group consistingof C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen;or V₂ is a bond;

W is NR_(S), O, S, S(O) or S(O)₂; or W is absent;

Q is NR₆, O, S, S(O) or S(O)₂;

X is N or CR₇;

Y is N or CR₈;

Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino, carbamimidoyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₄₋₈diacylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₂₋₆ dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl, heterocyclic,heteroaryl, hydroxyl, hydroxycarbamimidoyl, hydroxylamino, nitro andtetrazolyl, wherein C₁₋₈ alkyl, C₃₋₇ cycloalkyl, and heterocyclic areeach optionally substituted with 1, 2, 3 or 4 groups selected from thegroup consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₇ alkyl,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro, andwherein said C₁₋₇ alkyl is optionally substituted with amino; or

Z is a group of Formula (A):

wherein:

R₉ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl; and

R₁₀ is H, nitro or nitrile;

Ar₁ is aryl or heteroaryl each optionally substituted with R₁₁, R₁₂,R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the group consisting ofC₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, arylsulfonyl, carbamimidoyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,guanidinyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro,C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid, andthiol, and wherein C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, arylsulfonyl, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, heteroaryl, phenoxy and phenyl are optionallysubstituted with 1 to 5 substituents selected independently from thegroup consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy,C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy,wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₄ alkoxy and hydroxy; or

R₁₁ is a group of Formula (B):

wherein:

“p” and “r” are each independently 0, 1, 2 or 3; and R₁₆ is H, C₁₋₅acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₄ alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl or phenyl,and wherein the heteroaryl or phenyl optionally substituted with 1 to 5substituents selected independently from the group consisting of C₁₋₄alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl; and

R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected form the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyland nitro; or

two adjacent groups selected from the group consisting of R₁₂, R₁₃, R₁₄and R₁₅ together with the atoms to which they are attached form a 5-, 6-or 7-membered cycloalkyl, cycloalkenyl or heterocyclic group fused withAr₁, wherein the 5-, 6- or 7-membered group is optionally substitutedwith halogen;

R₁, R₇ and R₈ are each independently selected from the group consistingof H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano, C₃₋₇cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio and hydroxyl;

R₂ is selected from the group consisting of C₁₋₈ alkyl, amino, aryl,carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, halogen, heteroaryl and hydroxyl; and wherein C₁₋₈ alkyl,aryl or heteroaryl optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro; or

R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are each independently aryl orheteroaryl optionally substituted with 1 to 5 substituents selected fromthe group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, C₁₋₄alkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or

R₂ is a group of Formula (C):

wherein:

R₁₇ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl or OR₁₉; and R₁₈is F, Cl, Br, CN or NR₂OR₂₁; where R₁₉ is H, C₁₋₈ alkyl or C₃₋₇cycloalkyl, and R₂₀ and R₂₁ are each independently H, C₁₋₈ alkyl, C₃₋₇cycloalkyl, aryl or heteroaryl; or

R₂ is a group of Formula (D):

wherein:

G is:

i) —C(O)—, —C(O)NR₂₃—, —C(O)O—, —OC(O)NR₂₃—, —NR₂₃C(O)O—, —OC(O)—,—C(S)—, —C(S)NR₂₃—, —C(S)O—, —OC(S)—, —CR₂₃R₂₄—, —O—, —S—, —S(O)— or—S(O)₂— when D is CR₂R₃, or

ii) —CR₂₃R₂₄C(O)—, —C(O)—, —CR₂₃R₂₄C(O)NR₂₅—, —C(O)NR₂₃—, —C(O)O—,—C(S)—, —C(S)NR₂₃—, —C(S)O—, —CR₂₃R₂₄—, —S(O)₂—, or a bond when D isNR₂,

wherein R₂₃, R₂₄ and R₂₅ are each independently H or C₁₋₈ alkyl; and R₂₂is H, C₁₋₈ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl, heteroaryl, phenyland phenoxy are each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, and nitro;

R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy or hydroxyl; and

R₄, R₅ and R₆ are each independently H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl,wherein said C₁₋₈ alkyl is optionally substituted with C₁₋₄ alkoxy, C₃₋₇cycloalkyl, or heteroaryl.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising at least one compound of the present inventionand a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for thetreatment of a metabolic-related disorder in an individual comprisingadministering to the individual in need of such treatment atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of decreasingfood intake of an individual comprising administering to the individualin need thereof a therapeutically effective amount of a compound of thepresent invention or pharmaceutical composition thereof. One aspect ofthe present invention pertains to methods of inducing satiety in anindividual comprising administering to the individual in need thereof atherapeutically effective amount of a compound of the present inventionor pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of controllingor decreasing weight gain of an individual comprising administering tothe individual in need thereof a therapeutically effective amount of acompound of the present invention or pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of modulating aRUP3 receptor in an individual comprising contacting the receptor with acompound of the present invention. In some embodiments, the compound isan agonist for the RUP3 receptor. In some embodiments, the modulation ofthe RUP3 receptor is the treatment of a metabolic-related disorder. Someembodiments of the present invention include a method of modulating aRUP3 receptor in an individual comprising contacting the receptor with acompound of the present invention wherein the modulation of the RUP3receptor reduces food intake of the individual.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor induces satiety in the individual.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor controls or reduces weight gain of the individual.

One aspect of the present invention pertains to use of a compound of thepresent invention for production of a medicament for use in thetreatment of a metabolic-related disorder.

One aspect of the present invention pertains to use of a compound of thepresent invention for production of a medicament for use in decreasingfood intake in an individual.

One aspect of the present invention pertains to use of a compound of thepresent invention for production of a medicament for use of inducingsatiety in an individual.

One aspect of the present invention pertains to use of a compound of thepresent invention for production of a medicament for use in controllingor decreasing weight gain in an individual. One aspect of the presentinvention pertains to a compound of the present invention for use in amethod of treatment of the human or animal body by therapy.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of treatment of ametabolic-related disorder of the human or animal body by therapy.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of decreasing food intake of thehuman or animal body by therapy.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of inducing satiety of the humanor animal body by therapy.

One aspect of the present invention pertains to a compound of thepresent invention for use in a method of controlling or decreasingweight gain of the human or animal body by therapy. Some embodiments ofthe present invention pertain to methods wherein the human has a bodymass index of about 18.5 to about 45. In some embodiments, the human hasa body mass index of about 25 to about 45. In some embodiments, thehuman has a body mass index of about 30 to about 45. In someembodiments, the human has a body mass index of about 35 to about 45.

In some embodiments the individual is a mammal. In some embodiments themammal is a human.

In some embodiments, the metabolic-related disorder is hyperlipidemia,type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes(Type Ib), latent autoimmune diabetes in adults (LADA), early-onset type2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onsetdiabetes of the young (MODY), malnutrition-related diabetes, gestationaldiabetes, coronary heart disease, ischemic stroke, restenosis afterangioplasty, peripheral vascular disease, intermittent claudication,myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia,post-prandial lipemia, conditions of impaired glucose tolerance (IGT),conditions of impaired fasting plasma glucose, metabolic acidosis,ketosis, arthritis, obesity, osteoporosis, hypertension, congestiveheart failure, left ventricular hypertrophy, peripheral arterialdisease, diabetic retinopathy, macular degeneration, cataract, diabeticnephropathy, glomerulosclerosis, chronic renal failure, diabeticneuropathy, metabolic syndrome, syndrome X, premenstrual syndrome,coronary heart disease, angina pectoris, thrombosis, atherosclerosis,myocardial infarction, transient ischemic attacks, stroke, vascularrestenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,hypertrygliceridemia, insulin resistance, impaired glucose metabolism,conditions of impaired glucose tolerance, conditions of impaired fastingplasma glucose, obesity, erectile dysfunction, skin and connectivetissue disorders, foot ulcerations and ulcerative colitis, endothelialdysfunction and impaired vascular compliance.

In some embodiments, the metabolic-related disorder is type I diabetes,type II diabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. In some embodiments,the metabolic-related disorder is type II diabetes. In some embodiments,the metabolic-related disorder is hyperglycemia. In some embodiments,the metabolic-related disorder is hyperlipidemia. In some embodiments,the metabolic-related disorder is hypertriglyceridemia. In someembodiments, the metabolic-related disorder is type I diabetes. In someembodiments, the metabolic-related disorder is dyslipidemia. In someembodiments, the metabolic-related disorder is syndrome X.

One aspect of the present invention pertains to a method of producing apharmaceutical composition comprising admixing at least one compound, asdescribed herein, and a pharmaceutically acceptable carrier.

This application is related to two US Provisional Patent Applications,Ser. Nos. 60/486,728 filed Jul. 11, 2003; and 60/487,370 filed Jul. 14,2003, both which are incorporated by reference in their entirety.

Applicant reserves the right to exclude any one or more of the compoundsfrom any of the embodiments of the invention. Applicant additionallyreserves the right to exclude any disease, condition or disorder fromany of the embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows RT-PCR analysis of RUP3 expression in human tissues. Atotal of twenty-two (22) human tissues were analyzed.

FIG. 1B shows the cDNA Dot-Blot analysis of RUP 3 expression in humantissues.

FIG. 1C shows analysis of RUP3 by RT-PCR with isolated human pancreaticislets of Langerhans.

FIG. 1D shows analysis of RUP3 expression with cDNAs of rat origin byRT-PCR.

FIG. 2A shows a polyclonal anti-RUP3 antibody prepared in Rabbits.

FIG. 2B shows the expression of RUP3 in insulin-producing β cells ofpancreatic islets.

FIG. 3 shows in vitro functional activities of RUP3.

FIG. 4 shows a RUP3 RNA blot.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The scientific literature that has evolved around receptors has adopteda number of terms to refer to ligands having various effects onreceptors. For clarity and consistency, the following definitions willbe used throughout this patent document.

AGONISTS shall mean moieties that interact and activate the receptor,such as the RUP3 receptor and initiates a physiological orpharmacological response characteristic of that receptor. For example,when moieties activate the intracellular response upon binding to thereceptor, or enhance GTP binding to membranes.

AMINO ACID ABBREVIATIONS used herein are set out in TABLE 1:

TABLE 1 ALANINE ALA A ARGININE ARG R ASPARAGINE ASN N ASPARTIC ACID ASPD CYSTEINE CYS C GLUTAMIC ACID GLU E GLUTAMINE GLN Q GLYCINE GLY GHISTIDINE HIS H ISOLEUCINE ILE I LEUCINE LEU L LYSINE LYS K METHIONINEMET M PHENYLALANINE PHE F PROLINE PRO P SERINE SER S THREONINE THR TTRYPTOPHAN TRP W TYROSINE TYR Y VALINE VAL V ALANINE ALA A

The term ANTAGONISTS is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist.

Chemical Group, Moiety or Radical:

-   -   The term “C₁₋₅ acyl” denotes a C₁₋₅ alkyl radical attached to a        carbonyl wherein the definition of alkyl has the same definition        as described herein; some examples include but not limited to,        acetyl, propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl,        t-butanoyl (i.e., pivaloyl), pentanoyl and the like.    -   The term “C₁₋₅ acyloxy” denotes an acyl radical attached to an        oxygen atom wherein acyl has the same definition has described        herein; some examples include but not limited to acetyloxy,        propionyloxy, butanoyloxy, iso-butanoyloxy, sec-butanoyloxy,        t-butanoyloxy and the like.    -   The term “C₁₋₆ acylsulfonamide” refers to a C₁₋₆ acyl attached        directly to the nitrogen of the sulfonamide, wherein the        definitions for C₁₋₆ acyl and sulfonamide have the same meaning        as described herein, and a C₁₋₆ acylsulfonamide can be        represented by the following formula:

-   -    Some embodiments of the present invention are when        acylsulfonamide is a C₁₋₅ acylsulfonamide, some embodiments are        C₁₋₄ acylsulfonamide, some embodiments are C₁₋₃ acylsulfonamide,        and some embodiments are C₁₋₂ acylsulfonamide. Examples of an        acylsulfonamide include, but not limited to, acetylsulfamoyl        [—S(═O)₂NHC(═O)Me], propionylsulfamoyl [—S(═O)₂NHC(═O)Et],        isobutyrylsulfamoyl, butyrylsulfamoyl,        2-methyl-butyrylsulfamoyl, 3-methyl-butyrylsulfamoyl,        2,2-dimethyl-propionylsulfamoyl, pentanoylsulfamoyl,        2-methyl-pentanoylsulfamoyl, 3-methyl-pentanoylsulfamoyl,        4-methyl-pentanoylsulfamoyl, and the like.    -   The term “C₂₋₆ alkenyl” denotes a radical containing 2 to 6        carbons wherein at least one carbon-carbon double bond is        present, some embodiments are 2 to 4 carbons, some embodiments        are 2 to 3 carbons, and some embodiments have 2 carbons. Both E        and Z isomers are embraced by the term “alkenyl.” Furthermore,        the term “alkenyl” includes di- and tri-alkenyls. Accordingly,        if more than one double bond is present then the bonds may be        all E or Z or a mixtures of E and Z. Examples of an alkenyl        include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,        3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,        5-hexanyl, 2,4-hexadienyl and the like.    -   The term “C₁₋₄ alkoxy” as used herein denotes a radical alkyl,        as defined herein, attached directly to an oxygen atom. Examples        include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,        t-butoxy, iso-butoxy, sec-butoxy and the like.    -   The term “alkyl” denotes a straight or branched carbon radical        containing 1 to 8 carbons, some embodiments are 1 to 7 carbons,        some embodiments are 1 to 6 carbons, some embodiments are 1 to 3        carbons, and some embodiments are 1 or 2 carbons. Examples of an        alkyl include, but not limited to, methyl, ethyl, n-propyl,        iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl,        iso-pentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,        —CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃],        n-hexyl and the like.    -   The term C₁₋₆ or C₁₋₄ “alkylcarboxamido” or “alkylcarboxamide”        denotes a single C₁₋₆ or C₁₋₄ alkyl group attached to the        nitrogen or carbon of an amide group, wherein alkyl has the same        definition as found herein. The alkylcarboxamide may be        represented by the following:

-   -    Examples include, but not limited to, N-methylcarboxamide,        N-ethylcarboxamide, N-n-propylcarboxamide,        N-iso-propylcarboxamide, N-n-butylcarboxamide,        N-sec-butylcarboxamide, N-iso-butylcarboxamide,        N-t-butylcarboxamide and the like.    -   The term “C₁₋₃ alkylene” refers to a C₁₋₃ divalent straight        carbon group. In some embodiments C₁₋₃ alkylene refers to, for        example, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, and the like. In some        embodiments, C₁₋₃ alkylene refers to —CH—, —CHCH₂—, —CHCH₂CH₂—,        and the like wherein these examples relate generally to “A”.    -   The term “C₁₋₄ alkylsulfinyl” denotes a C₁₋₄ alkyl radical        attached to a sulfoxide radical of the formula: —S(O)— wherein        the alkyl radical has the same definition as described herein.        Examples include, but not limited to, methylsulfinyl,        ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl,        n-butylsulfinyl, sec-butylsulfinyl, iso-butylsulfinyl, t-butyl,        and the like.    -   The term “C₁₋₄ alkylsulfonamide” refers to the groups

-   -    wherein C₁₋₄ alkyl has the same definition as described herein.    -   The term “C₁₋₄ alkylsulfonyl” denotes a C₁₋₄ alkyl radical        attached to a sulfone radical of the formula: —S(O)₂— wherein        the alkyl radical has the same definition as described herein.        Examples include, but not limited to, methylsulfonyl,        ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl,        n-butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, t-butyl,        and the like.    -   The term “C₁₋₄ alkylthio” denotes a C₁₋₄ alkyl radical attached        to a sulfide of the formula: —S— wherein the alkyl radical has        the same definition as described herein. Examples include, but        not limited to, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl,        n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl,        sec-butylsulfanyl, iso-butylsulfanyl, t-butyl, and the like.    -   The term “C₁₋₄ alkylthiocarboxamide” denotes a thioamide of the        following formulae:

-   -    wherein C₁₋₄ alkyl has the same definition as described herein.    -   The term “C₁₋₄ alkylthioureyl” denotes the group of the formula:        —NC(S)N— wherein one are both of the nitrogens are substituted        with the same or different C₁₋₄ alkyl groups and alkyl has the        same definition as described herein. Examples of an        alkylthioureyl include, but not limited to, CH₃NHC(S)NH—,        NH₂C(S)NCH₃—, (CH₃)₂N(S)NH—, (CH₃)₂N(S)NH—, (CH₃)₂N(S)NCH₃—,        CH₃CH₂NHC(S)NH—, CH₃CH₂NHC(S)NCH₃—, and the like.    -   The term “C₁₋₄ alkylureyl” denotes the group of the formula:        —NC(O)N— wherein one are both of the nitrogens are substituted        with the same or different C₁₋₄ alkyl group wherein alkyl has        the same definition as described herein. Examples of an        alkylureyl include, but not limited to, CH₃NHC(O)NH—,        NH₂C(O)NCH₃—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NCH₃—,        CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.    -   The term “C₂₋₆ alkynyl” denotes a radical containing 2 to 6        carbons and at least one carbon-carbon triple bond, some        embodiments are 2 to 4 carbons, some embodiments are 2 to 3        carbons, and some embodiments have 2 carbons. Examples of an        alkynyl include, but not limited to, ethynyl, 1-propynyl,        2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,        2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,        3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term “alkynyl”        includes di- and tri-ynes.    -   The term “amino” denotes the group —NH₂.    -   The term “C₁₋₄ alkylamino” denotes one alkyl radical attached to        an amino radical wherein the alkyl radical has the same meaning        as described herein. Some examples include, but not limited to,        methylamino, ethylamino, n-propylamino, iso-propylamino,        n-butylamino, sec-butylamino, iso-butylamino, t-butylamino, and        the like. Some embodiments are “C₁₋₂ alkylamino.”    -   The term “aryl” denotes an aromatic ring radical containing 6 to        10 ring carbons. Examples include phenyl and naphthyl.    -   The term “arylalkyl” defines a C₁-C₄ alkylene, such as —CH₂—,        —CH₂CH₂— and the like, which is further substituted with an aryl        group. Examples of an “arylalkyl” include benzyl, phenethylene        and the like.    -   The term “arylcarboxamido” denotes a single aryl group attached        to the nitrogen of an amide group, wherein aryl has the same        definition as found herein. The example is N-phenylcarboxamide.    -   The term “arylureyl” denotes the group —NC(O)N— where one of the        nitrogens are substituted with an aryl.    -   The term “benzyl” denotes the group —CH₂C₆H₅.    -   The term “carbamimidoyl” refers to a group of the following        chemical formula:

-   -    and in some embodiments, one or both hydrogens are replaced        with another group. For example, one hydrogen can be replaced        with a hydroxyl group to give a N-hydroxycarbamimidoyl group, or        one hydrogen can be replaced with an alkyl group to give        N-methylcarbamimidoyl, N-ethylcarbamimidoyl,        N-propylcarbamimidoyl, N-butylcarbamimidoyl, and the like.    -   The term “carbo-C₁₋₆-alkoxy” refers to a C₁₋₆ alkyl ester of a        carboxylic acid, wherein the alkyl group is as defined herein.        Examples include, but not limited to, carbomethoxy, carboethoxy,        carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy,        carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy,        carbo-iso-pentoxy, carbo-t-pentoxy, carbo-neo-pentoxy,        carbo-n-hexyloxy, and the like.    -   The term “carboxamide” refers to the group —CONH₂.    -   The term “carboxy” or “carboxyl” denotes the group —CO₂H; also        referred to as a carboxylic acid group.    -   The term “cyano” denotes the group —CN.    -   The term “C₃₋₇ cycloalkenyl” denotes a non-aromatic ring radical        containing 3 to 6 ring carbons and at least one double bond;        some embodiments contain 3 to 5 carbons; some embodiments        contain 3 to 4 carbons. Examples include cyclopropenyl,        cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and        the like.    -   The term “C₃₋₇ cycloalkyl” denotes a saturated ring radical        containing 3 to 6 carbons; some embodiments contain 3 to 5        carbons; some embodiments contain 3 to 4 carbons. Examples        include cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl,        cyclohexyl, cycloheptyl and the like.    -   The term “C₃₋₆ cycloalkylene” refers to a divalent cycloalkyl        radical, where cycloalkyl is as defined herein, containing 3 to        6 carbons; some embodiments contain 3 to 5 carbons; some        embodiments contain 3 to 4 carbons. In some embodiments, the two        bonding groups are on the same carbon, for example:

-   -    In some embodiments, the two bonding groups are on different        carbons.    -   The term “C₄₋₈ diacylamino” denotes an amino group bonded with        two acyl groups defined herein wherein the acyl groups may be        the same or different, such as:

-   -    Examples of C₄₋₈ diacylamino groups include, but limited to,        diacetylamino, dipropionylamino, acetylpropionylamino and the        like.    -   The term “C₂₋₆ dialkylamino” denotes an amino substituted with        two of the same or different alkyl radicals wherein alkyl        radical has the same definition as described herein. Some        examples include, but not limited to, dimethylamino,        methylethylamino, diethylamino, methylpropylamino,        methylisopropylamino, ethylpropylamino, ethylisopropylamino,        dipropylamino, propylisopropylamino and the like. Some        embodiments are “C₂₋₄ dialkylamino.”    -   The term “C₁₋₄ dialkylcarboxamido” or “C₁₋₄ dialkylcarboxamide”        denotes two alkyl radicals, that are the same or different,        attached to an amide group, wherein alkyl has the same        definition as described herein. A C₁₋₄ dialkylcarboxamido may be        represented by the following groups:

-   -    wherein C₁₋₄ has the same definition as described herein.        Examples of a dialkylcarboxamide include, but not limited to,        N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,        N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the        like.    -   The term “C₂₋₆ dialkylsulfonamide” refers to one of the        following groups shown below:

-   -    wherein C₁₋₃ has the same definition as described herein, for        example but not limited to, methyl, ethyl, n-propyl, isopropyl,        and the like.    -   The term “C₂₋₆ dialkylthiocarboxamido” or “C₂₋₆        dialkylthiocarboxamide” denotes two alkyl radicals, that are the        same or different, attached to a thioamide group, wherein alkyl        has the same definition as described herein. A C₁₋₄        dialkylthiocarboxamido may be represented by the following        groups:

-   -    Examples of a dialkylthiocarboxamide include, but not limited        to, N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide        and the like.    -   The term “C₂₋₆ dialkylsulfonylamino” refers to an amino group        bonded with two C₁₋₃ alkylsulfonyl groups as defined herein.    -   The term “ethynylene” refers to the carbon-carbon triple bond        group as represented below:

-   -   The term “formyl” refers to the group —CHO.    -   The term “guanidine” refers to a group of the following chemical        formula:

-   -   The term “C₁₋₄ haloalkoxy” denotes a haloalkyl, as defined        herein, which is directly attached to an oxygen atom. Examples        include, but not limited to, difluoromethoxy, trifluoromethoxy,        2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.    -   The term “C₁₋₄ haloalkyl” denotes an C₁₋₄ alkyl group, defined        herein, wherein the alkyl is substituted with one halogen up to        fully substituted and a fully substituted C₁₋₄ haloalkyl can be        represented by the formula C_(n)L_(2n+1) wherein L is a halogen        and “n” is 1, 2, 3 or 4; when more than one halogen is present        then they may be the same or different and selected from the        group consisting of F, Cl, Br and I, preferably F. Examples of        C₁₋₄ haloalkyl groups include, but not limited to, fluoromethyl,        difluoromethyl, trifluoromethyl, chlorodifluoromethyl,        2,2,2-trifluoroethyl, pentafluoroethyl and the like.    -   The term “C₁₋₄ haloalkylcarboxamide” denotes an alkylcarboxamide        group, defined herein, wherein the alkyl is substituted with one        halogen up to fully substituted represented by the formula        C_(n)L_(2n+1) wherein L is a halogen and “n” is 1, 2, 3 or 4.        When more than one halogen is present they may be the same or        different and selected from the group consisting of F, Cl, Br        and I, preferably F.    -   The term “C₁₋₄ haloalkylsulfinyl” denotes a haloalkyl radical        attached to a sulfoxide group of the formula: —S(O)— wherein the        haloalkyl radical has the same definition as described herein.        Examples include, but not limited to, trifluoromethylsulfinyl,        2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the        like.    -   The term “C₁₋₄ haloalkylsulfonyl” denotes a haloalkyl radical        attached to a sulfone group of the formula: —S(O)₂— wherein        haloalkyl has the same definition as described herein. Examples        include, but not limited to, trifluoromethylsulfonyl,        2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl and the        like.    -   The term “C₁₋₄ haloalkylthio” denotes a haloalkyl radicaol        directly attached to a sulfur wherein the haloalkyl has the same        meaning as described herein. Examples include, but not limited        to, trifluoromethylthio (i.e., CF₃S—), 1,1-difluoroethylthio,        2,2,2-trifluoroethylthio and the like.    -   The term “halogen” or “halo” denotes to a fluoro, chloro, bromo        or iodo group.    -   The term “C₁₋₂ heteroalkylene” refers to a C₁₋₂ alkylene bonded        to a heteroatom selected from O, S, S(O), S(O)₂ and NH. Some        represented examples include, but not limited to, the groups of        the following formulae:

-   -    and the like.    -   The term “heteroaryl” denotes an aromatic ring system that may        be a single ring, two fused rings or three fused rings wherein        at least one ring carbon is replaced with a heteroatom selected        from, but not limited to, the group consisting of O, S and N        wherein the N can be optionally substituted with H, C₁₋₄ acyl or        C₁₋₄ alkyl. Examples of heteroaryl groups include, but not        limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl,        pyrimidinyl, triazinyl, quinoline, benzoxazole, benzothiazole,        1H-benzimidazole, isoquinoline, quinazoline, quinoxaline and the        like. In some embodiments, the heteroaryl atom is O, S, NH,        examples include, but not limited to, pyrrole, indole, and the        like. Other examples include, but not limited to, those in TABLE        2A, TABLE 4, and the like.    -   The term “heterocyclic” denotes a non-aromatic carbon ring        (i.e., cycloalkyl or cycloalkenyl as defined herein) wherein        one, two or three ring carbons are replaced by a heteroatom        selected from, but not limited to, the group consisting of O, S,        N, wherein the N can be optionally substituted with H, C₁₋₄ acyl        or C₁₋₄ alkyl, and ring carbon atoms optionally substituted with        oxo or a thiooxo thus forming a carbonyl or thiocarbonyl group.        The heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered        containing ring. Examples of a heterocyclic group include but        not limited to aziridin-1-yl, aziridin-2-yl, azetidin-1-yl,        azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-4-yl,        morpholin-4-yl, piperzin-1-yl, piperzin-4-yl, pyrrolidin-1-yl,        pyrrolidin-3-yl, [1,3]-dioxolan-2-yl and the like. Additional        examples of heterocyclic groups are shown in TABLES 2B, 2C, 2D,        2E, 2F and 2G, infra.    -   The term “heterocyclic-carbonyl” denotes a heterocyclic group,        as defined herein, directly bonded to the carbon of a carbonyl        group (i.e., C═O). In some embodiments, a ring nitrogen of the        heterocyclic group is bonded to the carbonyl group forming an        amide. Examples include, but not limited to,

-   -    and the like.

In some embodiments, a ring carbon is bonded to the carbonyl groupforming a ketone group. Examples include, but not limited to,

-   -    and the like.    -   The term “heterocyclic-oxy” refers to a heterocyclic group, as        defined herein, that is directly bonded to an oxygen atom.        Examples include the following:

-   -    and the like.    -   The term “heterocyclicsulfonyl” denotes a heterocyclic group, as        defined herein, with a ring nitrogen where the ring nitrogen is        bonded directly to an SO₂ group forming an sulfonamide. Examples        include, but not limited to,

-   -    and the like.    -   The term “hydroxyl” refers to the group —OH.    -   The term “hydroxylamino” refers to the group —NHOH.    -   The term “nitro” refers to the group —NO₂.    -   The term “C₄₋₇ oxo-cycloalkyl” refers to a C₄₋₇ cycloalkyl, as        defined herein, wherein one of the ring carbons is replaced with        a carbonyl. Examples of C₄₋₇ oxo-cycloalkyl include, but are not        limited to, 2-oxo-cyclobutyl, 3-oxo-cyclobutyl,        3-oxo-cyclopentyl, 4-oxo-cyclohexyl, and the like and        represented by the following structures respectively:

-   -   The term “perfluoroalkyl” denotes the group of the formula        —C_(n)F_(2n+1); stated differently, a perfluoroalkyl is an alkyl        as defined herein wherein the alkyl is fully substituted with        fluorine atoms and is therefore considered a subset of        haloalkyl. Examples of perfluoroalkyls include CF₃, CF₂CF₃,        CF₂CF₂CF₃, CF(CF₃)₂, CF₂CF₂CF₂CF₃, CF₂CF(CF₃)₂, CF(CF₃)CF₂CF₃        and the like.    -   The term “phenoxy” refers to the group C₆H_(S)O—.    -   The term “phenyl” refers to the group C₆H₅—.    -   The term “phosphonooxy” refers to a group with the following        chemical structure:

-   -   The term “sulfonamide” refers to the group —SO₂NH₂.    -   The term “sulfonic acid” refers to the group —SO₃H.    -   The term “tetrazolyl” refers to the five membered heteroaryl of        the following formulae:

-   -   In some embodiments, the tetrazolyl group is further substituted        at either the 1 or 5 position resepectively with a group        selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ haloalkyl        and C₁₋₃ alkoxy.    -   The term “thiol” denotes the group —SH.

CODON shall mean a grouping of three nucleotides (or equivalents tonucleotides) which generally comprise a nucleoside (adenosine (A),guanosine (G), cytidine (C), uridine (U) and thymidine (T)) coupled to aphosphate group and which, when translated, encodes an amino acid.

COMPOSITION shall mean a material comprising at least two compounds ortwo components; for example, and without limitation, a PharmaceuticalComposition is a Composition comprising a compound of the presentinvention and a pharmaceutically acceptable carrier.

CONTACT or CONTACTING shall mean bringing the indicated moietiestogether, whether in an in vitro system or an in vivo system. Thus,“contacting” a RUP3 receptor with a compound of the invention includesthe administration of a compound of the present invention to anindividual, preferably a human, having a RUP3 receptor, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or more purified preparation containing a RUP3receptor.

IN NEED OF PROPHYLAXIS OR TREATMENT as used herein refers to a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner, etc. inthe case of humans; veterinarian in the case of animals, includingnon-human mammals) that an individual or animal requires or will benefitfrom prophylaxis or treatment. This judgment is made based on a varietyof factors that are in the realm of a caregiver's expertise, but thatincludes the knowledge that the individual or animal is ill, or will beill, as the result of a disease, condition or disorder that is treatableby the compounds of the invention. In general, “in need of prophylaxis”refers to the judgment made by the caregiver that the individual willbecome ill. In this context, the compounds of the invention are used ina protective or preventive manner. However, “in need of treatment”refers to the judgment of the caregiver that the individual is alreadyill, therefore, the compounds of the present invention are used toalleviate, inhibit or ameliorate the disease, condition or disorder.

INDIVIDUAL as used herein refers to any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

INHIBIT or INHIBITING, in relationship to the term “response” shall meanthat a response is decreased or prevented in the presence of a compoundas opposed to in the absence of the compound.

INVERSE AGONISTS shall mean moieties that bind the endogenous form ofthe receptor or to the constitutively activated form of the receptor,and which inhibit the baseline intracellular response initiated by theactive form of the receptor below the normal base level of activitywhich is observed in the absence of agonists or partial agonists, ordecrease GTP binding to membranes. Preferably, the baselineintracellular response is inhibited in the presence of the inverseagonist by at least 30%, more preferably by at least 50%, and mostpreferably by at least 75%, as compared with the baseline response inthe absence of the inverse agonist.

LIGAND shall mean an endogenous, naturally occurring molecule specificfor an endogenous, naturally occurring receptor.

As used herein, the terms MODULATE or MODULATING shall mean to refer toan increase or decrease in the amount, quality, response or effect of aparticular activity, function or molecule.

PHARMACEUTICAL COMPOSITION shall mean a composition comprising at leastone active ingredient, whereby the composition is amenable toinvestigation for a specified, efficacious outcome in a mammal (forexample, without limitation, a human). Those of ordinary skill in theart will understand and appreciate the techniques appropriate fordetermining whether an active ingredient has a desired efficaciousoutcome based upon the needs of the artisan.

THERAPEUTICALLY EFFECTIVE AMOUNT as used herein refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician, which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Compounds of the Present Invention:

One aspect of the present invention encompasses trisubstituted aryl andheteroaryl derivatives as shown in Formula (I):

or a pharmaceutically acceptable salt, or N-oxide thereof; wherein Ar₁,V₁, V₂, W, Q, X, Y, Z, A, B, D, E,

, and R₁ have the same definitions as described herein, supra and infra.

Some embodiments of the present invention encompass trisubstituted aryland heteroaryl derivatives as shown in Formula (I) wherein:

A and B are each independently C₁₋₃ alkylene optionally substituted with1 to 4 substituents selected from the group consisting of C₁₋₃ alkyl,C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen;

D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂;

E is N, C or CR₄;

is a single bond when E is N or CR₄, or a double bond when E is C;

V₁ is selected from the group consisting of C₁₋₃ alkylene, ethynyleneand C₁₋₂ heteroalkylene optionally substituted with 1 to 4 substituentsselected from the group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy,cyano, C₁₋₃ haloalkyl and halogen; or V₁ is a bond;

V₂ is selected from the group consisting of C₁₋₃ alkylene optionallysubstituted with 1 to 4 substituents selected from the group consistingof C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen;or V₂ is a bond;

W is NR₅, O, S, S(O) or S(O)₂; or W is absent;

Q is NR₆, O, S, S(O) or S(O)₂;

X is N or CR₇;

Y is N or CR₈;

Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₄₋₈diacylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₂₋₆ dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl, heterocyclic,heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl, wherein C₁₋₈alkyl is optionally substituted with 1, 2, 3 or 4 groups selected fromthe group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro; or

Z is a group of Formula (A):

-   -   wherein:    -   R₉ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl; and    -   R₁₀ is H, nitro or nitrile;    -   Ar₁ is aryl or heteroaryl each optionally substituted with R₁₁,        R₁₂, R₁₃, R₁₄, and R₁₅; where R₁₁ is selected from the group        consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄        alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, amino, arylsulfonyl,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,        C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkylthio, heterocyclic, heterocyclicsulfonyl, heteroaryl,        hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl,        sulfonamide and sulfonic acid, and wherein C₁₋₅ acyl, C₁₋₄        alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfonamide, alkylsulfonyl,        arylsulfonyl, heteroaryl, phenoxy or phenyl optionally        substituted with 1 to 5 substituents selected independently from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl,        C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        heteroaryl, heterocyclic, hydroxyl, nitro and phenyl; or    -   R₁₁ is a group of Formula (B):

-   -   -   wherein:        -   “p” and “r” are each independently 0, 1, 2 or 3; and        -   R₁₆ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄            alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,            carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇            cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl or            phenyl, and wherein the heteroaryl or phenyl optionally            substituted with 1 to 5 substituents selected independently            from the group consisting of C₁₋₄ alkoxy, amino, C₁₋₄            alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄            haloalkoxy, C₁₋₄ haloalkyl and hydroxyl;

R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected form the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyland nitro; or two adjacent groups selected from the group consisting ofR₁₂, R₁₃, R₁₄ and R₁₅ form a 5, 6 or 7 membered cycloalkyl, cycloalkenylor heterocyclic group with Ar₁ wherein the 5, 6 or 7 membered group isoptionally substituted with halogen;

R₁, R₇ and R₈ are each independently selected from the group consistingof H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano, C₃₋₇cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio and hydroxyl;

R₂ is selected from the group consisting of H, C₁₋₈ alkyl, amino, aryl,carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, halogen, heteroaryl and hydroxyl; and wherein C₁₋₈ alkyl,aryl or heteroaryl optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro; or

R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are each independently aryl orheteroaryl optionally substituted with 1 to 5 substituents selected fromthe group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, C₁₋₄alkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or

R₂ is a group of Formula (C):

-   -   wherein:    -   R₁₇ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl or OR₁₉;        and R₁₈ is F, Cl, Br, CN or NR₂OR₂₁; where R₁₉ is H, C₁₋₈ alkyl        or C₃₋₇ cycloalkyl, and R₂₀ and R₂₁ are each independently H,        C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl or heteroaryl; or R₂ is a        group of Formula (D):

-   -   wherein:        -   G is:        -   i) C(O), C(O)NR₂₃, C(O)O, OC(O), C(S), C(S)NR₂₃, C(S)O,            OC(S), CR₂₃R₂₄, O, S, S(O) or S(O)₂ when D is CR₂R₃, or        -   ii) C(O), C(O)NR₂₃, C(O)O, C(S), C(S)NR₂₃, C(S)O, CR₂₃R₂₄ or            S(O)₂ when D is NR₂, where R₂₃ and R₂₄ are each            independently H or C₁₋₈ alkyl; and        -   R₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl or heteroaryl            optionally substituted with 1 to 5 substituents selected            from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄            alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide,            C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄            alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄            alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy,            carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₈            dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆            dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄            alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄            haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl,            C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino and            nitro;

R₃ is H, C₁₋₈ alkyl, C₁ alkoxy or hydroxyl; and

R₄, R₅ and R₆ are each independently H, or C₁₋₈ alkyl; or apharmaceutically acceptable salt, hydrate or solvate thereof.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment.

Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, may also be providedseparately or in any suitable subcombination.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

It is understood and appreciated that compounds of Formula (I) may haveone or more chiral centers, and therefore can exist as enantiomersand/or diastereomers. The invention is understood to extend to andembrace all such enantiomers, diastereomers and mixtures thereof,including but not limited, to racemates. Accordingly, some embodimentsof the present invention pertain to compounds of Formula (I) andformulae used throughout this disclosure that are R enantiomers.Further, some embodiments of the present invention pertain to compoundsof Formula (I) and formulae used throughout this disclosure that are Senantiomers. In examples where more than one chiral center is present,then, some embodiments of the present invention include compounds thatare RS or SR enantiomers. In further embodiments, compounds of thepresent invention are RR or SS enantiomers. It is understood thatcompounds of Formula (I) and formulae used throughout this disclosureare intended to represent all individual enantiomers and mixturesthereof, unless stated or shown otherwise.

Many geometric isomers of olefins, C═N double bonds, disubstitutedcycloalkyl (i.e., 1,4-cyclohexyl groups), and the like can also bepresent in the compounds described herein, and all such stable isomersare contemplated in the present invention. Cis and trans geometricisomers of the compounds of the present invention are described and maybe isolated as a mixture of isomers or as separated isomeric forms.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers, and the like. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution. It is understood that the various tautomeric forms arewithin the scope of the compounds of the present invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates and/or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include deuterium and tritium.

In some embodiments, X and Y are each independently N or CH, providedthat if either X or Y is CH then the other is N.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein W is NR_(S). In some embodiments, R₅ is H.

In some embodiments, W is NH.

In some embodiments compounds of the present invention can berepresented by Formula (Ia) as illustrated below:

wherein each variable in Formula (Ia) has the same meaning as describedherein, supra and infra. In some embodiments, V₁ is a bond. In stillfurther embodiments, both V₁ and V₂ are bonds.

In some embodiments, W is O,

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein W is O and can be represented by Formula (Ic) asillustrated below:

wherein each variable in Formula (Ic) has the same meaning as describedherein, supra and infra. Some embodiments of the present inventionpertain to compounds of Formula (Ic) wherein V₁ is absent. In someembodiments, Q is an oxygen atom. In still further embodiments, Q is anoxygen atom and both V₁ and V₂ are bonds.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein W is S, S(O) or S(O)₂.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein W is absent.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Q is NR₆.

In some embodiments, R₆ is H.

In some embodiments, R₆ is C₁₋₈ alkyl.

In some embodiments, R₆ is selected from the group consisting of methyl,ethyl, isopropyl, and n-propyl.

In some embodiments, R₆ is isopropyl.

In some embodiments, R₆ is C₃₋₇ cycloalkyl.

In some embodiments, R₆ is selected from the group consisting ofcyclopropyl, cyclobutyl, and cyclopentyl.

In some embodiments, R₆ is cyclopropyl

In some embodiments, Q is NH.

In some embodiments, R₆ is cyclopropylmethyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Q is NH and can be represented by Formula (Ie) asillustrated below:

wherein each variable in Formula (Ie) has the same meaning as describedherein, supra and infra. In some embodiments, V₂ is a bond.

In some embodiments, Q is O.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Q is O (i.e., an oxygen atom) and can be representedby Formula (Ig) as illustrated below:

wherein each variable in Formula (Ig) has the same meaning as describedherein, supra and infra. In some embodiments, V₂ is a bond. In someembodiments, V₂ is —CH₂—. In still further embodiments, V₂ is —CH₂CH₂—.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Q is S, S(O) or S(O)₂.

In some embodiments, Q is S.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein V₁ is a bond.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein V₂ is a bond.

In some embodiments, V₁ and V₂ are both a bond. Some embodiments of thepresent invention pertain to compounds of Formula (I) wherein V₂ is—CH₂—.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein V₂ is —CH₂CH₂—.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein A and B are independently C₁₋₂ alkylene optionallysubstituted with 1 to 4 substituents selected from the group consistingof C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein both A and B are C₁ alkylene groups wherein A and Bare optionally substituted with 1 to 2 methyl groups.

In some embodiments, A and B are both —CH₂—. In some embodiments,compounds of the present invention can be represented by Formula (Ik) asshown below:

wherein each variable in Formula (Ik) has the same meaning as describedherein, supra and infra.

In some embodiments, both A and B are —CH₂— and E is CH.

In some embodiments, both A and B are —CH₂—, E is CH, and D is N—R₂.

In some embodiments, A is —CH₂CH₂— and B is —CH₂—.

In some embodiments, A is —CH₂CH₂— and B is —CH₂—, and E is CH.

In some embodiments, A is —CH₂CH₂— and B is —CH₂—, E is CH and D isN—R₂.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein A is a C₁ alkylene group and B is a C₂ alkylenegroup wherein A is optionally substituted with 1 to 2 methyl groups andB is optionally substituted with 1 to 4 methyl groups.

In some embodiments, compounds of the present invention can berepresented by Formulae (Im) and (In) respectively as shown below:

wherein each variable in Formulae (Im) and (In) has the same meaning asdescribed herein, supra and infra. In some embodiments, A is —CH₂— and Bis —CH₂CH₂—. In further embodiments, A is —CH₂—, B is —CH₂CH₂—, and V₂is —CH₂— or —CH₂CH₂—. Some embodiments of the present invention pertainto compounds of Formula (I) wherein A is a C₁ alkylene group and B is aC₃ alkylene group wherein A is optionally substituted with 1 to 2 methylgroups and B is optionally substituted with 1 to 4 methyl groups. Insome embodiments, A is —CH₂— or —CH— and B is —CH₂CH₂CH₂— and can berepresented by Formulae (Ip) and (Iq) respectively as shown below:

wherein each variable in Formulae (Ip) and (Iq) has the same meaning asdescribed herein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein A is a C₂ alkylene group and B is a C₁ alkylenegroup wherein A is optionally substituted with 1 to 4 methyl groups andB is optionally substituted with 1 to 2 methyl groups. In someembodiments, A is —CHCH₂— and B is —CH₂—; these embodiments can berepresented by Formula (It) as shown below:

wherein each variable in Formula (It) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein A is CH₂ and B is —CH₂CH₂—, —CH₂CH(CH₃)—,—CH(CH₃)CH₂—, —CH₂CH(CF₃)— or —CH(CF₃)CH₂—. In some embodiments,compounds of the invention are represented by Formulae (Iv), (Iw) and(Ix) as shown below:

wherein each variable in Formulae (Iv), (Ivy) and (Ix) has the samemeaning as described herein, supra and infra. In some embodiments, D isN—R₂. In further embodiments, D is N—R₂ wherein R₂ is represented byFormula (D). In still further embodiments, D is N—R₂ wherein R₂ is—C(O)OC₁₋₈ alkyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein A is a C₃ alkylene group and B is a C₁ alkylenegroup wherein A is optionally substituted with 1 to 4 methyl groups andB is optionally substituted with 1 to 2 methyl groups. In someembodiments, A is —CHCH₂CH₂— and B is —CH₂— and represented by Formulae(IIa) as shown below:

wherein each variable in Formulae (IIa) has the same meaning asdescribed herein, supra and infra.

In some embodiments, both A and B are —CH₂CH₂—.

In some embodiments, both A and B are —CH₂CH₂— and E is CH.

In some embodiments, both A and B are —CH₂CH₂—, E is CH, and D is N—R₂.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein both A and B are C₂ alkylene groups wherein A and Bare optionally substituted with 1 to 4 methyl groups.

In some embodiments, A is —CH₂CH₂— or —CHCH₂— and B is —CH₂CH₂—. In someembodiments, compounds of the present invention can be represented byFormulae (IIc) and (IId) as shown below:

wherein each variable in Formulae (IIc) and (IId) has the same meaningas described herein, supra and infra. In some embodiments, A and B areboth —CH₂CH₂—, D is N—R₂, and E is CR₄; these embodiments arerepresented by Formula (III) as shown below:

wherein each variable in Formula (III) has the same meaning as describedherein, supra and infra. In some embodiments, compounds have the Formula(III) and R₄ is H. In further embodiment, V₂ is a bond. In still furtherembodiments, V₂ is —CH₂— or —CH₂CH₂—.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein A is a C₂ alkylene group and B is a C₃ alkylenegroup wherein A and B are optionally substituted with 1 to 4 methylgroups. In some embodiments, A is —CH₂CH₂— or —CHCH₂— and B is—CH₂CH₂CH₂— and can be represented by Formulae (IIh) and (IIi) as shownbelow:

wherein each variable in Formulae (IIh) and (IIi) has the same meaningas described herein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein A is a C₃ alkylene group and B is a C₂ alkylenegroup wherein A and B are optionally substituted with 1 to 4 methylgroups. In some embodiments, A is —CHCH₂CH₂— and B is —CH₂CH₂—; theseembodiments can be represented by Formula (IIk) as shown below:

wherein each variable in Formula (IIk) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein both A and B are C₃ alkylene groups wherein A and Bare optionally substituted with 1 to 4 methyl groups. In someembodiments, A is —CH₂CH₂CH₂— or —CHCH₂CH₂— and B is —CH₂CH₂CH₂— and arerepresented by Formula (IIm) and (IIn) respectively as shown below:

wherein each variable in Formulae (IIm) and (IIn) has the same meaningas described herein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein

is a single bond.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein E is a nitrogen atom (i.e., N).

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein E is CR₄. In some embodiments, R₄ is H and can berepresented by Formula (IIp) as shown below:

wherein each variable in Formula (IIp) has the same meaning as describedherein, supra and infra. In further embodiments, V₂ is a bond andrepresented by Formula (IIr):

wherein each variable in Formula (IIr) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the presentinvention are of Formula (IIr) and Q is NH. In some embodiments,compounds are of Formula (IIr) and Q is O (i.e., an oxygen atom). Someembodiments of the present invention pertain to compounds of Formula (I)wherein

a double bond. It is understood that when

is a double bond then E is C (i.e., a carbon atom) and not N (i.e., anitrogen atom).

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein V₂ is a CH₂ or CH₂CH₂ group.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein V₁ is a bond and V₂ is a CH₂ or CH₂CH₂ group.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is CR₂R₃ and can be represented by Formula (IIt)as shown below:

wherein each variable in Formula (IIt) has the same meaning as describedherein, supra and infra. In some embodiments, compounds of the inventionare of Formula (IIt) and R₂ is selected from the group consisting of H,amino, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, halogen and hydroxyl. In some embodiments, R₂ is—NR₂₃C(O)O—(C₁₋₈ alkyl) or —OC(O)NR₂₃—(C₁₋₈ alkyl). In some embodiments,R₂ is selected from the group consisting of OCH₃, OCH₂CH₃, OCH₂CH₂CH₃,OCH(CH₃)₂, OCH₂(CH₂)₂CH₃, amino, carboxamide, carboxy, cyano,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCF₃, OCHF₂, CF₃, CHF₂and F. In some embodiments, R₂ is C₁₋₈ alkyl, aryl or heteroaryloptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino andnitro. In some embodiments, R₂ is selected from the group consisting ofCH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃,CH₂(CH₂)₃CH₃. In some embodiments, R₂ is selected from the groupconsisting of CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃,CH₂CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₂CH₃, CH₂OCH(CH₃)₂, CH₂OCH₂CH(CH₃)₂, CH₂CO₂H,CH₂CH₂CO₂H, CH₂OH, CH₂CH₂OH and CH₂CH₂CH₂OH. In some embodiments, R₂ isselected from the group consisting of CH₂SCH₃, CH₂SCH₂CH₃,CH₂SCH₂CH₂CH₃, CH₂SCH(CH₃)₂, CH₂SCH₂(CH₂)₂CH₃, CH₂CH₂SCH₃,CH₂CH₂SCH₂CH₃, CH₂CH₂SCH₂CH₂CH₃, CH₂CH₂SCH(CH₃)₂, CH₂CH₂SCH₂(CH₂)₂CH₃,CH₂S(O)CH₃, CH₂S(O)CH₂CH₃, CH₂S(O)CH₂CH₂CH₃, CH₂S(O)CH(CH₃)₂,CH₂S(O)CH₂(CH₂)₂CH₃, CH₂CH₂S(O)CH₃, CH₂CH₂S(O)CH₂CH₃,CH₂CH₂S(O)CH₂CH₂CH₃, CH₂CH₂S(O)CH(CH₃)₂, CH₂CH₂S(O)CH₂(CH₂)₂CH₃,CH₂S(O)₂CH₃, CH₂S(O)₂CH₂CH₃, CH₂S(O)₂CH₂CH₂CH₃, CH₂S(O)₂CH(CH₃)₂,CH₂S(O)₂CH₂(CH₂)₂CH₃, CH₂CH₂S(O)₂CH₃, CH₂CH₂S(O)₂CH₂CH₃,CH₂CH₂S(O)₂CH₂CH₂CH₃, CH₂CH₂S(O)₂CH(CH₃)₂ and CH₂CH₂S(O)₂CH₂(CH₂)₂CH₃.In some embodiments, R₂ is selected from the group consisting ofCH₂OCH₂-cyclopropyl, CH₂OCH₂-cyclobutyl, CH₂OCH₂-cyclopentyl,CH₂OCH₂-cyclohexyl, CH₂OCH₂CH₂-cyclopropyl, CH₂OCH₂CH₂-cyclobutyl,CH₂OCH₂CH₂-cyclopentyl, CH₂OCH₂CH₂-cyclohexyl, CH₂CH₂OCH₂-cyclopropyl,CH₂CH₂OCH₂-cyclobutyl, CH₂CH₂OCH₂-cyclopentyl, CH₂CH₂OCH₂-cyclohexyl,CH₂CH₂OCH₂CH₂-cyclopropyl, CH₂CH₂OCH₂CH₂-cyclobutyl,CH₂CH₂OCH₂CH₂-cyclopentyl and CH₂CH₂OCH₂CH₂-cyclohexyl. In someembodiments, R₂ is selected from the group consisting of1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,4-triazol-5-yl and 1,2,4-triazol-1-yl,3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,3-ethyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl,5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,3-methyl-1,2,4-triazol-5-yl, 3-ethyl-1,2,4-triazol-5-yl,3-methyl-1,2,4-triazol-1-yl, 3-ethyl-1,2,4-triazol-1-yl,5-methyl-1,2,4-triazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.

In some embodiments R₂ is a heteroaryl comprising 5-atoms in thearomatic ring and are represented by the following formulae:

TABLE 2A

wherein the 5-membered heteroaryl is bonded at any available position ofthe ring, for example, a imidazolyl ring can be bonded at one of thering nitrogens (i.e., imidazol-1-yl group) or at one of the ring carbons(i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl group). In someembodiments R₂ is a 5-membered heteroaryl, for example but not limitedto those shown in TABLE 2A, optionally substituted with 1 to 4substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino,C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro.

In some embodiments R₂ is a heteroaryl comprising 5-atoms in thearomatic ring and are represented by the following formulae:

wherein the 5-membered heteroaryl is bonded at any available position ofthe ring as described above. In some embodiments, R₂ is a 5-memberedheteroaryl optionally substituted with 1 to 4 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro.

In some embodiments R₂ is a heterocyclic group represented, for example,by the formulae in TABLE 2B.

TABLE 2B

It is understood that any one of the heterocyclic groups shown in TABLES2B to 2E may be bonded at any ring carbon or ring nitrogen as allowed bythe respective formula unless otherwise specified. For example, a2,5-dioxo-imidazolidinyl group may be bonded at the ring carbon or ateither of the two ring nitrogens to give the following formulaerespectively:

In some embodiments R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2C.

TABLE 2C

In some embodiments R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2D.

TABLE 2D

In some embodiments R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2E.

TABLE 2E

In some embodiments R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2F wherein the C₁₋₆ alkyl group on the respectivering nitrogen atoms may be the same or different.

TABLE 2F

In some embodiments R₂ is a heterocyclic represented, for example, bythe formulae in TABLE 2G wherein the C₁₋₆ alkyl group on the respectivering nitrogen atoms may be the same or different.

TABLE 2G

Some embodiments of the present invention pertain to compounds ofFormula (IIt) and R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are independentlyaryl or heteroaryl optionally substituted with 1 to 5 substituentsselected from the group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyland nitro. In some embodiments, Ar₂ is a heteroaryl and Ar₃ is phenyl.In some embodiments, the heteroaryl and said phenyl are optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, cyano, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, halogen, hydroxyl and nitro.

In some embodiments Ar₂ is a heteroaryl comprising 5-atoms in thearomatic ring and are represented by the following formulae shown inTABLE 3.

TABLE 3

wherein the 5-membered heteroaryl is bonded at any position of the ring,for example, a imidazolyl ring can be bonded at one of the ringnitrogens (i.e., imidazol-1-yl group) or at one of the ring carbons(i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl group) and Ar₃ isbonded to any remaining available ring atom. In some embodiments Ar₂ isa heteroaryl and Ar₃ is phenyl. In some embodiments, Ar₂ is a phenyl andAr₃ is heteroaryl (such as a heteroaryl selected from TABLE 2A, supra).In some embodiments the heteroaryl and phenyl are optionally substitutedwith 1 to 5 substituents selected from the group consisting of H, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen,hydroxyl and nitro.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is CR₂R₃, or R₂ is Formula (C):

wherein:

R₁₇ is C₁₋₈ alkyl or C₃₋₇ cycloalkyl; and R₁₈ is F, Cl, Br or CN. Insome embodiments, R₁₇ is C₁₋₈ alkyl and R₁₈ is F, Cl or CN.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is CR₂R₃ and R₂ is Formula (D):

wherein:

G is C(O), C(O)NR₂₃, C(O)O, OC(O), C(S), C(S)NR₂₃, C(S)O, OC(S),CR₂₃R₂₄, O, S, S(O) or S(O)₂; where R₂₃ and R₂₄ are independently H orC₁₋₈ alkyl; and R₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl or heteroaryloptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₈dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₂ is Formula (D) and G is C(O), C(O)NR₂₃, C(O)O,OC(O), C(S), C(S)NR₂₃, C(S)O, OC(S) or CR₂₃R₂₄. In some embodiments, R₂₂is C₁₋₈ alkyl optionally substituted with 1 to 5 substituents selectedfrom the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl. In some embodiments, Formula (D) (i.e.,-G-R₂₂) is selected from the group consisting of C(O)CH₃, C(O)CH₂CH₃,C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃, C(O)C(CH₃)₃,C(O)CH₂C(CH₃)₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃),CH₂(CH₂)₂CH₃, C(CH₃)₃, CH₂(CH₂)₃CH₃, C(O)NHCH₃, C(O)NHCH₂CH₃,C(O)NHCH₂CH₂CH₃, C(O)NHCH(CH₃)₂, C(O)NHCH₂(CH₂)₂CH₃, C(O)N(CH₃)₂,C(O)N(CH₃)CH₂CH₃, C(O)NH(CH₂CH₃)₂, CO₂CH₃, CO₂CH₂CH₃, CO₂CH₂CH₂CH₃,CO₂CH(CH₃)₂ and CO₂CH₂(CH₂)₂CH₃.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₂ is Formula (D) and G is C(O), C(O)NR₂₃, C(O)O,OC(O), C(S), C(S)NR₂₃, C(S)O, OC(S) or CR₂₃R₂₄. In some embodiments, R₂₂is phenyl optionally substituted with 1 to 5 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₂ is Formula (D) and G is C(O), C(O)NR₂₃, C(O)O,OC(O), C(S), C(S)NR₂₃, C(S)O, OC(S) or CR₂₃R₂₄. In some embodiments, R₂₂is heteroaryl optionally substituted with 1 to 5 substituents selectedfrom the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl. In some embodiments, R₂₂ is a5-membered heteroaryl, for example, as shown in TABLE 2A supra. In someembodiments, R₂₂ is 1-methyl-1H-imidazole-4-yl or2,4-dimethyl-thiazole-5-yl.

In some embodiments, R₂₂ is a 6-membered heteroaryl, for example, the6-membered heteroaryls as shown in TABLE 4:

TABLE 4

wherein the heteroaryl group is bonded at any ring carbon. In someembodiments R₂₂ is selected from the group consisting of pyridinyl,pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, R₂₂ ispyridinyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₂₃ and R₂₄ are independently H or C₁₋₂ alkyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₂ is Formula (D) and G is O, S, S(O) or S(O)₂. Insome embodiments, R₂₂ is C₁₋₈ alkyloptionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, halogen and hydroxyl. In someembodiments, Formula (D) (i.e., -G-R₂₂) is selected from the groupconsisting of: OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂(CH₂)₂CH₃,SCH₃, SCH₂CH₃, SCH₂CH₂CH₃, SCH(CH₃)₂, SCH₂(CH₂)₂CH₃, S(O)CH₃,S(O)CH₂CH₃, S(O)CH₂CH₂CH₃, S(O)CH(CH₃)₂, S(O)CH₂(CH₂)₂CH₃, S(O)₂CH₃,S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂ and S(O)₂CH₂(CH₂)₂CH₃.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₂ is Formula (D) and G is O, S, S(O) or S(O)₂. Insome embodiments, R₂₂ is phenyl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, halogen and hydroxyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₂ is Formula (D) and G is O, S, S(O) or S(O)₂. Insome embodiments, R₂₂ is heteroaryl optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, halogen and hydroxyl. In someembodiments, R₂₂ is a 5-membered heteroaryl, for example, as shown inTABLE 2A supra. In some embodiments, R₂₂ is a 6-membered heteroaryl, asshown in TABLE 4 supra. In some embodiments R₂₂ is selected from thegroup consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.In some embodiments, R₂₂ is pyridinyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₃ is H.

In some embodiments, D is N—R₂.

Some embodiments of the present invention pertain to compounds wherein Dis N—R₂ and is represented by Formula (IIv):

wherein each variable in Formula (IIv) has the same meaning as describedherein, supra and infra. In some embodiments, R₂ is C₁₋₈ alkyl, aryl orheteroaryl optionally substituted with 1 to 5 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro. In some embodiments, R₂ is pyridyl. In someembodiments, R₂ is 2-pyridyl. In some embodiments, R₂ is selected fromthe group consisting of CH₂CH₂C(CH₃)₃, CH₂CH₂CH(CH₃)₂ and CH₂(CH₂)₄—CH₃.In some embodiments, R₂ is selected from the group consisting of: CH₃,CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃ andCH₂(CH₂)₃CH₃. In some embodiments, R₂ is selected from the groupconsisting of CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃,CH₂CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₂CH₃, CH₂OCH(CH₃)₂, CH₂OCH₂CH(CH₃)₂, CH₂CO₂H,CH₂CH₂CO₂H, CH₂OH, CH₂CH₂OH and CH₂CH₂CH₂OH. In some embodiments, R₂ isselected from the group consisting of CH₂SCH₃, CH₂SCH₂CH₃,CH₂SCH₂CH₂CH₃, CH₂SCH(CH₃)₂, CH₂SCH₂(CH₂)₂CH₃, CH₂CH₂SCH₃,CH₂CH₂SCH₂CH₃, CH₂CH₂SCH₂CH₂CH₃, CH₂CH₂SCH(CH₃)₂, CH₂CH₂SCH₂(CH₂)₂CH₃,CH₂S(O)CH₃, CH₂S(O)CH₂CH₃, CH₂S(O)CH₂CH₂CH₃, CH₂S(O)CH(CH₃)₂,CH₂S(O)CH₂(CH₂)₂CH₃, CH₂CH₂S(O)CH₃, CH₂CH₂S(O)CH₂CH₃,CH₂CH₂S(O)CH₂CH₂CH₃, CH₂CH₂S(O)CH(CH₃)₂, CH₂CH₂S(O)CH₂(CH₂)₂CH₃,CH₂S(O)₂CH₃, CH₂S(O)₂CH₂CH₃, CH₂S(O)₂CH₂CH₂CH₃, CH₂S(O)₂CH(CH₃)₂,CH₂S(O)₂CH₂(CH₂)₂CH₃, CH₂CH₂S(O)₂CH₃, CH₂CH₂S(O)₂CH₂CH₃,CH₂CH₂S(O)₂CH₂CH₂CH₃, CH₂CH₂S(O)₂CH(CH₃)₂ and CH₂CH₂S(O)₂CH₂(CH₂)₂CH₃.In some embodiments, R₂ is CH₂-cyclopropyl. In some embodiments, R₂ isselected from the group consisting of CH₂OCH₂-cyclopropyl,CH₂OCH₂-cyclobutyl, CH₂OCH₂-cyclopentyl, CH₂OCH₂-cyclohexyl,CH₂OCH₂CH₂-cyclopropyl, CH₂OCH₂CH₂-cyclobutyl, CH₂OCH₂CH₂-cyclopentyl,CH₂OCH₂CH₂-cyclohexyl, CH₂CH₂OCH₂-cyclopropyl, CH₂CH₂OCH₂-cyclobutyl,CH₂CH₂OCH₂-cyclopentyl, CH₂CH₂OCH₂-cyclohexyl,CH₂CH₂OCH₂CH₂-cyclopropyl, CH₂CH₂OCH₂CH₂-cyclobutyl,CH₂CH₂OCH₂CH₂-cyclopentyl and CH₂CH₂OCH₂CH₂-cyclohexyl. In someembodiments, R₂ is selected from the group consisting of1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,4-triazol-5-yl and 1,2,4-triazol-1-yl,3-methyl-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,3-ethyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl,5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl,3-methyl-1,2,4-triazol-5-yl, 3-ethyl-1,2,4-triazol-5-yl,3-methyl-1,2,4-triazol-1-yl, 3-ethyl-1,2,4-triazol-1-yl,5-methyl-1,2,4-triazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.

In some embodiments, compounds are of Formula (IIv) and R₂ is aheteroaryl comprising 5-atoms in the aromatic ring selected from thegroup shown in Table 2A. In some embodiments R₂ is a 5-memberedheteroaryl optionally substituted with 1 to 4 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro. In some embodiments R₂ is a heteroaryl selectedfrom the group, but not limited to the group, in TABLE 2A. In someembodiments, R₂ is a 5-membered heteroaryl optionally substituted with 1to 4 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino and nitro. In some embodiments R₂ is a heterocyclic groupselected from the groups shown in TABLE 2B to TABLE 2G.

Some embodiments of the present invention pertain to compounds ofFormula (IIv) and R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are independentlyaryl or heteroaryl optionally substituted with 1 to 5 substituentsselected from the group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyland nitro. In some embodiments Ar₂ is a heteroaryl comprising 5-atoms inthe aromatic ring and selected from the group shown in TABLE 3. In someembodiments Ar₂ is a heteroaryl and Ar₃ is phenyl. In some embodiments,Ar₂ is a phenyl and Ar₃ is heteroaryl (such as a heteroaryl selectedfrom TABLE 2A or TABLE 4, supra). In some embodiments, the heteroaryland phenyl are optionally substituted with 1 to 5 substituents selectedfrom the group consisting of H, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is N—R₂. In some embodiments, R₂ is Formula (C):

wherein:

R₁₇ is C₁₋₈ alkyl or C₃₋₇ cycloalkyl; and R₁₈ is F, Cl, Br or CN. Insome embodiments, R₁₇ is C₁₋₈ alkyl and R₁₈ is F, Cl or CN.

In some embodiments, R₂ is selected from the group consisting ofmethoxycarbonyl, ethoxycarbonyl, iso-propoxycarbonyl, n-propoxycarbonyl,n-butoxycarbonyl, tert-butoxycarbonyl, iso-butoxycarbonyl, andn-pentyloxycarbonyl. In some embodiments, R₂ is iso-propoxycarbonyl ortert-butoxycarbonyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is N—R₂. In some embodiments, R₂ is Formula (D):

wherein:

G is C(O), C(O)NR₂₃, C(O)O, C(S), C(S)NR₂₃, C(S)O, CR₂₃R₂₄ or S(O)₂;where R₂₃ and R₂₄ are independently H or C₁₋₈ alkyl; and R₂₂ is C₁₋₈alkyl, C₃₋₇ cycloalkyl, phenyl or heteroaryl optionally substituted with1 to 5 substituents selected from the group consisting of C₁₋₅ acyl,C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,hydroxyl, hydroxylamino and nitro.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is N—R₂. In some embodiments, R₂ is Formula (D)and R₂₂ is C₁₋₈ alkyl optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₇alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl. In some embodiments, D is N—R₂ where R₂is of Formula (D) (i.e., -G-R₂₂) and -G-R₂₂ is selected from the groupconsisting of C(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂,C(O)CH₂CH₂CH₂CH₃, C(O)C(CH₃)₃, C(O)CH₂C(CH₃)₃, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, C(CH₃)₃, CH₂(CH₂)₃CH₃,C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NHCH₂CH₂CH₃, C(O)NHCH(CH₃)₂,C(O)NHCH₂(CH₂)₂CH₃, C(O)N(CH₃)₂, C(O)N(CH₃)CH₂CH₃, C(O)NH(CH₂CH₃)₂,CO₂CH₃, CO₂CH₂CH₃, CO₂CH₂CH₂CH₃, CO₂CH(CH₃)₂ and CO₂CH₂(CH₂)₂CH₃.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is N—R₂. In some embodiments, R₂ is Formula (D)and R₂₂ is phenyl optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₇alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is N—R₂. In some embodiments, R₂ is Formula (D)and R₂₂ is heteroaryl optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, halogen and hydroxyl. In some embodiments, R₂₂ is selectedfrom the group consisting of pyridinyl, pyridazinyl, pyrimidinyl andpyrazinyl. In some embodiments, R₂₂ is pyridinyl. In some embodiments,R₂ is a group of Formula (D):

wherein:

G is —CR₂₃R₂₄C(O)—, —C(O)—, —CR₂₃R₂₄C(O)NR₂₃—, —C(O)NR₂₃—, —C(O)O—,—C(S)—, —C(S)NR₂₃—, —C(S)O—, —CR₂₃R₂₄—, —S(O)₂—, or a bond; wherein R₂₃and R₂₄ are each independently H or C₁₋₈ alkyl; and

R₂₂ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl, phenyl and phenoxyare each optionally substituted with 1 to 5 substituents selected fromthe group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, and nitro.

In some embodiments, Formula (D) is —C(O)OR₂₂.

In some embodiments, Formula (D) is —C(O)R₂₂.

In some embodiments, Formula (D) is —CR₂₃R₂₄-R₂₂.

In some embodiments, Formula (D) is —R₂₂ (i.e., -G- is a bond).

In some embodiments, Formula (D) is —S(O)₂R₂₂.

In some embodiments, Formula (D) is —CR₂₃R₂₄C(O)R₂₂.

In some embodiments, Formula (D) is —CR₂₃R₂₄C(O)NR₂₅R₂₂.

In some embodiments, R₂ is —C(O)OR₂₂ and R₂₂ is C₁₋₈ alkyl, C₃₋₇cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino,carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic,hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl,phenyl and phenoxy are each optionally substituted with 1 to 5substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.

In some embodiments, R₂ is —C(O)OR₂₂ and R₂₂ is C₁₋₈ alkyl, or C₃₋₇cycloalkyl each optionally substituted with 1 to 5 substituents selectedfrom the group consisting of C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylsulfonyl, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl,phenyl, phenoxy, and sulfonic acid.

In some embodiments, R₂ is —C(O)OR₂₂ and R₂₂ is C₁₋₈ alkyl, or C₃₋₇cycloalkyl wherein said C₃₋₇ cycloalkyl is optionally substituted with 1to 5 substituents selected from the group consisting of C₁₋₄ alkoxy,C₁₋₇ alkyl, carboxy, C₂₋₈ dialkylamino, and halogen.

In some embodiments, R₂ is —C(O)OR₂₂ and R₂₂ is C₁₋₈ alkyl, or C₃₋₇cycloalkyl.

In some embodiments, R₂ is —C(O)R₂₂ and R₂₂ is C₁₋₈ alkyl, C₃₋₇cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino,carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic,hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl,phenyl and phenoxy are each optionally substituted with 1 to 5substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.

In some embodiments, R₂ is —C(O)R₂₂ and R₂₂ is C₁₋₈ alkyl, heteroaryl,or heterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of H, C₁₋₄ alkoxy, C₁₋₇ alkyl, amino,carboxy, halogen, heteroaryl, hydroxyl, phenoxy, and sulfonic acid,wherein said C₁₋₇ alkyl and phenoxy are optionally substituted with 1 to5 substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.

In some embodiments, R₂ is —CH₂R₂₂, or —R₂₂ and R₂₂ is C₁₋₈ alkyl, C₃₋₇cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl,amino, carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl,heterocyclic, hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein saidC₁₋₇ alkyl, phenyl and phenoxy are each optionally substituted with 1 to5 substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.

In some embodiments, R₂ is —CH₂R₂₂, or —R₂₂, and R₂₂ is C₁₋₈ alkyl, C₃₋₇cycloalkyl, or heteroaryl each optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₂₋₆alkenyl, C₁₋₄ alkoxy, carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇cycloalkyl, and hydroxyl. R₂ is —S(O)₂R₂₂ and R₂₂ is C₁₋₈ alkyl, C₃₋₇cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino,carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic,hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl,phenyl and phenoxy are each optionally substituted with 1 to 5substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.

In some embodiments, R₂ is —S(O)₂R₂₂ and R₂₂ is C₁₋₈ alkyl, orheteroaryl and said heteroaryl is optionally substituted with 1 to 5C₁₋₇ alkyl.

In some embodiments, R₂ is —CR₂₃R₂₄C(O)R₂₂ and wherein R₂₃ and R₂₄ areeach independently H or C₁₋₈ alkyl; and R₂₂ is C₁₋₈ alkyl, C₃₋₇cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino,carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic,hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl,phenyl and phenoxy are each optionally substituted with 1 to 5substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.

In some embodiments, R₂ is —CR₂₃R₂₄C(O)R₂₂ and wherein R₂₃ and R₂₄ areeach independently H or C₁₋₈ alkyl; and R₂₂ is phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylsulfonyl, cyano, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, halogen, heteroaryl, and phenyl.

R₂ is —CR₂₃R₂₄C(O)NR₂₅R₂₂ and wherein R₂₃, R₂₄ and R₂₅ are eachindependently H or C₁₋₈ alkyl; and R₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl,phenyl, heteroaryl, or heterocyclic each optionally substituted with 1to 5 substituents selected from the group consisting of C₂₋₆ alkenyl,C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl, phenyl and phenoxyare each optionally substituted with 1 to 5 substituents selected fromthe group consisting of amino, C₁₋₄ haloalkoxy, and heterocyclic.

In some embodiments, R₂ is —CH₂C(O)NHR₂₂ and wherein R₂₂ is phenyloptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ haloalkyl, and halogen.

In some embodiments, A and B are both —CH₂CH₂—, D is NR₂, E is CR₄,

is a single bond and V₁ and V₂ are both single bonds; these embodimentscan be represented by Formula (IIx) as shown below:

wherein each variable in Formula (IIx) has the same meaning as describedherein, supra and infra. In some embodiments, compounds are of Formula(IIx) and W is NR_(S). In some embodiments, R₅ is H. In someembodiments, Z is cyano. In further embodiments, Q is NR₆, O, S, S(O) orS(O)₂. In still further embodiments, Q is NH or O.

In some embodiments, compounds of the present invention are of Formula(IIx) wherein R₂ is Formula (D); these embodiments can be represented byFormula (IIy) as shown below:

wherein each variable in Formula (IIy) has the same meaning as describedherein, supra and infra. In some embodiments, G is C(O), C(O)NR₂₃,C(O)O, C(S), C(S)NR₂₃, C(S)O, CR₂₃R₂₄ or S(O)₂. In some embodiments, Gis C(O) and can be represented by Formula (IIz) as shown below:

wherein each variable in Formula (IIz) has the same meaning as describedherein, supra and infra. In some embodiments, G is C(O)O and can berepresented by Formula (Ma) as shown below:

wherein each variable in Formula (IIIa) has the same meaning asdescribed herein, supra and infra.

In some embodiments, compounds are of either Formula (IIz) or (IIIa) andR₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl or heteroaryl optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro.

In some embodiments, compounds are of either Formula (IIz) or (IIIa) andR₂₂ is C₁₋₈ alkyl optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro.

In some embodiments, compounds are of either Formula (IIz) or (IIIa) andR₂₂ is phenyl optionally substituted with 1 to 5 substituents selectedfrom the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₇alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro. In some embodiments, the phenyl is substituted with 1 to 4substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carboxamide, carboxy, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio and halogen. Insome embodiments, the phenyl is substituted with 1 to 4 substituentsselected from the group consisting of C₁₋₄ alkylsulfonyl, C₁₋₄haloalkylsulfonyl and halogen.

In some embodiments, compounds are of either Formula (IIz) or (IIIa) andR₂₂ is heteroaryl optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro. In some embodiments, the heteroaryl is substituted with 1 to 4substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carboxamide, carboxy, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio and halogen. Insome embodiments, the heteroaryl is substituted with 1 to 4 substituentsselected from the group consisting of C₁₋₄ alkylsulfonyl, C₁₋₄haloalkylsulfonyl and halogen. In some embodiments, the heteroaryl is a5-memebered heteroaryl, for example, as shown in TABLE 2A, supra. Insome embodiments, the heteroaryl is a 6-membered heteroaryl, forexample, as shown in TABLE 4, supra. In some embodiments, the heteroarylis selected from the group consisting of pyridinyl, pyridazinyl,pyrimidinyl and pyrazinyl. In some embodiments, the heteroaryl ispyridinyl.

In some embodiments, R₂₂ is 1-methyl-1H-imidazole-4-yl, or2,4-dimethyl-thiazole-5-yl.

In some embodiments, compounds are of Formula (IIy), (IIx) or (IIIa) andW is NR₅. In some embodiments, R₅ is H. In some embodiments, Z is cyano.In further embodiments, Q is NR₆, O, S, S(O) or S(O)₂. In still furtherembodiments, Q is NH or O.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein D is O, S, S(O) or S(O)₂.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₂₃ and R₂₄ are independently H or C₁₋₂ alkyl. Insome embodiments, R₂₃ and R₂₄ are H.

In some embodiments, Z is selected from the group consisting of C₁₋₅acyl, C₁₋₈ alkyl, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, amino,carbamimidoyl, cyano, C₃₋₇ cycloalkyl, heterocyclic, andhydroxycarbamimidoyl, wherein C₁₋₈ alkyl, C₃₋₇ cycloalkyl, andheterocyclic are each optionally substituted with 1, 2, 3 or 4 groupsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, formyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen,hydroxyl, hydroxylamino and nitro, and wherein said C₁₋₇ alkyl isoptionally substituted with amino.

In some embodiments, Z is selected from the group consisting of C₁₋₅acyl, C₁₋₈ alkyl, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, amino,carbamimidoyl, cyano, C₃₋₇ cycloalkyl, heterocyclic, andhydroxycarbamimidoyl, wherein said heterocyclic is optionallysubstituted with a —CH₂NH₂ group.

In some embodiments, Z is selected from the group consisting of C(O)CH₃,C(O)CH₂CH₃, CH₃, CH₂CH₃, C≡CH, NHS(O)₂CH₃, amino, carbamimidoyl, cyano,cyclopropyl, 4,5-dihydro-1H-imidazol-2-yl,5-aminomethyl-4,5-dihydro-oxazol-2-yl, and hydroxycarbamimidoyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Z is selected from the group consisting of C₁₋₅acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, carboxamide,carboxy, cyano, formyl, aryl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide,heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl. In someembodiments, Z is selected from the group consisting of formyl,NHC(O)CH₃, NHC(O)CH₂CH₃, NHC(O)CH(CH₃)₂, CH₃, CH₂CH₃, CH(CH₃)₂,CH₂CH₂CH₂CH₃, NHC(O)CF₃, carboxy, cyano, CF₃, CF₂CF₃, nitro and1H-tetrazol-5-yl. In some embodiments, Z is selected from the groupconsisting of carboxy, CF₃, nitro and 1H-tetrazol-5-yl. In someembodiments, Z is cyano. In still further embodiments, Z is formyl [i.e.—C(O)H].

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Z is Formula (A):

wherein:

R₉ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl; and R¹⁰ is H, nitro or nitrile.In some embodiments, R₉ is H or C₁₋₈ alkyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₁, R₇ and R₈ are independently selected from thegroup consisting of H, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, amino,C₃₋₇ cycloalkyl and C₁₋₄ haloalkyl. In some embodiments, R₁, R₇ and R₈are independently H, halogen or amino. In still further embodiments, R₁,R₇ and R₈ are H.

In some embodiments, Ar₁ is aryl or heteroaryl each optionallysubstituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selectedfrom the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, carbamimidoyl, carboxamide,carboxy, cyano, C₂₋₆ dialkylamino, halogen, heterocyclic,heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl,and sulfonamide, and wherein C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylsulfonamide, alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₃₋₇ cycloalkyloxy, C₂₋₆dialkylamino, C₂₋₆ dialkylcarboxamide, heteroaryl, heterocyclic,hydroxyl, phenyl, and phosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄alkylcarboxamide are each optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₄ alkoxy andhydroxy; and

R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected form the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, carbamimidoyl, carboxamide, cyano,C₂₋₆ dialkylamino, and halogen.

In some embodiments, Ar₁ is aryl.

In some embodiments, Ar₁ is phenyl optionally substituted with R₁₁, R₁₂,R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the group consisting ofC₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆dialkylamino, halogen, heterocyclic, heterocyclic-oxy,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and sulfonamide,and wherein C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,and heteroaryl are each optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, carboxy, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ areeach independently selected form the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide, cyano, C₂₋₆ dialkylamino,and halogen.

In some embodiments, Ar₁ is phenyl optionally substituted with R₁₁, R₁₂,R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the group consisting ofC₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆dialkylamino, halogen, heterocyclic, heterocyclic-oxy,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and sulfonamide,and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ areeach independently selected form the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide, cyano, C₂₋₆ dialkylamino,and halogen.

In some embodiments, Ar₁ is phenyl optionally substituted with R₁₁, R₁₂,R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the group consisting ofC₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆dialkylamino, halogen, heterocyclic, heterocyclic-oxy,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and sulfonamide,and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ areeach independently selected form the group consisting of C₁₋₈ alkyl, andhalogen.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is phenyl. In some embodiments, the phenyl isoptionally substituted with R₁₁. In some embodiments, R₁₁ is selectedfrom the group consisting of H, C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₃₋₇cycloalkyl, halogen and sulfonamide. In some embodiments, R₁₁ isselected from the group consisting of C(O)CH₃, C(O)CH₂CH₃,C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃CH₃, CH₂(CH₂)₄CH₃, CH₂(CH₂)₅CH₃,C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NHCH₂CH₂CH₃, C(O)NHCH(CH₃)₂,C(O)NHCH₂(CH₂)₂CH₃, CCH, S(O)₂NHCH₃, S(O)₂NHCH₂CH₃, S(O)₂NHCH₂CH₂CH₃,S(O)₂NHCH(CH₃)₂, S(O)₂NHCH₂(CH₂)₂CH₃, S(O)₂NHCH(CH₃)CH₂CH₃, S(O)CH₃,S(O)CH₂CH₃, S(O)CH₂CH₂CH₃, S(O)CH(CH₃)₂, S(O)CH₂(CH₂)₂CH₃,S(O)CH(CH₃)CH₂CH₃, S(O)₂CH₃, S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂,S(O)₂CH₂(CH₂)₂CH₃, S(O)₂CH(CH₃)CH₂CH₃, SCH₃, SCH₂CH₃, SCH₂CH₂CH₃,SCH(CH₃)₂ and SCH₂(CH₂)₂CH₃. In some embodiments, R₁₁ is selected fromthe group consisting of amino, arylsulfonyl, carboxy, cyano, C₃₋₇cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl and C₁₋₄haloalkylthio. In some embodiments, R₁₁ is selected from the groupconsisting of phenylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, Cl, F, Br, OCF₃, OCHF₂, OCH₂CF₃, CF₃, CHF₂, CH₂CF₃, SCF₃,SCHF₂ and SCH₂CF₃. In some embodiments, R₁₁ is selected from the groupconsisting of heterocyclic, heteroaryl, C₄₋₇ oxo-cycloalkyl, phenoxy andphenyl. In some embodiments, R₁₁ is selected from the group consistingof morpholin-4-yl, thiomorpholin-4-yl, 1-oxo-1λ⁴-thiomorpholin-4-yl,1,1-Dioxo-1λ⁶-thiomorpholin-4-yl, piperazin-1-yl,4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl,4-propyl-piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl,2,5-dioxo-imidazolidin-4-yl, 2,4-dioxo-thiazolidin-5-yl,4-oxo-2-thioxo-thiazolidin-5-yl, 3-methyl-2,5-dioxo-imidazolidin-4-yl,3-methyl-2,4-dioxo-thiazolidin-5-yl,3-methyl-4-oxo-2-thioxo-thiazolidin-5-yl,3-ethyl-2,5-dioxo-imidazolidin-4-yl, 3-ethyl-2,4-dioxo-thiazolidin-5-yl,and 3-ethyl-4-oxo-2-thioxo-thiazolidin-5-yl. In some embodiments, R₁₁ isselected from the group consisting of 1H-imidazol-4-yl,[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,pyrrol-1-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl,oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl, [1,3,4]thiadiazol-2-yl,[1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl, tetrazol-1-yl,pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl,pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and[1,2,3]thiadiazol-4-yl. In some embodiments, R₁₁ is C₁₋₈ alkyl or C₁₋₄alkoxy optionally substituted with 1 to 5 substituents selectedindependently from the group consisting of C₁₋₄ alkoxy, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,cyano, heterocyclic, hydroxyl and phenyl. In some embodiments, R₁₁ isC₁₋₄ alkylsulfonyl optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₄ alkoxy,carboxamide, heteroaryl, heterocyclic and phenyl. In some embodiments,the C₁₋₄ alkylsulfonyl is substituted with the heteroaryl group. In someembodiments, the heteroaryl group is selected from the group consistingof 1H-imidazol-4-yl, [1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl,[1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl,imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl,tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl,1,3-dioxo-1,3-dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl. In someembodiments, R₁₁ is arylsulfonyl, heteroaryl, phenoxy or phenyloptionally substituted with 1 to 5 substituents selected independentlyfrom the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carboxamide, carboxy, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio and hydroxyl. In some embodiments, R₁₁ isarylsulfonyl, heteroaryl, phenoxy or phenyl optionally substituted with1 to 5 substituents selected independently from the group consisting ofC₁₋₄ alkoxy, C₁₋₈ alkyl, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyland hydroxyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is phenyl. In some embodiments, the phenyl isoptionally substituted with R₁₁. In some embodiments, R₁₁ is a group ofFormula (B):

wherein:

“p” and “r” are independently 0, 1, 2 or 3; and R₁₆ is H, C₁₋₅ acyl,C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl or phenyl, andwherein the heteroaryl or phenyl may be optionally substituted with 1 to5 substituents selected independently from the group consisting of C₁₋₄alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl. In someembodiments, p=0 and r=0. In some embodiments, R₁₆ is heteroaryl orphenyl optionally substituted with 1 to 5 substituents selectedindependently from the group consisting of C₁₋₄ alkoxy, amino, C₁₋₄alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl and hydroxyl. In some embodiments, the heteroaryl isselected from the group consisting of 1H-imidazol-4-yl,[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl, oxazol-5-yl,oxazol-2-yl, [1,3,4]oxadiazol-2-yl, [1,3,4]thiadiazol-2-yl,[1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl, tetrazol-1-yl,pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl,pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and[1,2,3]thiadiazol-4-yl. In some embodiments, p=0 and r=1. In someembodiments, R₁₆ is carbo-C₁₋₆-alkoxy or carboxy. In some embodiments,p=2 and r=1. In some embodiments, R₁₆ is H, C₁₋₅ acyl or C₁₋₈ alkyl.Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is phenyl. In some embodiments, the phenyl isoptionally substituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅. In someembodiments, R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ are independently selected fromthe group consisting of H, C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, halogen, C₁₋₄ haloalkoxy and C₁₋₄haloalkyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is phenyl and R₁₁ is substituted at the paraposition on the phenyl; these embodiments can be represented by Formula(Mc) as shown below:

wherein each variable in Formula (Mc) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is phenyl and two adjacent R₁₁, R₁₂, R₁₃, R₁₄,and R₁₅ groups together with the atoms to which they are attached form a5-, 6- or 7-membered cycloalkyl, cycloalkenyl or heterocyclic groupfused with Ar₁, wherein the 5-, 6- or 7-membered group is optionallysubstituted with halogen. In some embodiments, the phenyl and twoadjacent R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ groups form a 5-, 6- or 7-memberedcycloalkyl as represented in TABLE 5:

TABLE 5

wherein “a” is 1, 2 or 3 to give a 5-, 6- or 7-membered cycloalkyl fusedtogether with the phenyl group where two of the ring carbons are sharedbetween the cycloalkyl and phenyl group. In some embodiments, 1, 2, or 3ring carbons are replaced by a heteroatom selected from, but not limitedto, O, S, and N, wherein N is substituted with H or C₁₋₄ alkyl. In someembodiments, the two adjacent groups form a 5 membered heterocyclicgroup with the phenyl group. In some embodiments, the 5 memberedheterocyclic group with the phenyl group together is a2,3-dihydro-benzofuran-5-yl or benzo[1,3]dioxol-5-yl group. In someembodiments, the two adjacent groups form a 6 membered heterocyclicgroup with the phenyl group. In some embodiments, the 6 memberedheterocyclic group with the phenyl group together is a2,3-dihydro-benzo[1,4]dioxin-6-yl or 2,3-dihydro-benzo[1,4]dioxin-2-ylgroup. In some embodiments, the two adjacent groups form a 7 memberedheterocyclic group with the phenyl group. In some embodiments, the 7membered heterocyclic group with the phenyl group together is a3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl group.

In some embodiments, Ar₁ is heteroaryl.

In some embodiments, Ar₁ is pyridyl optionally substituted with R₁₁,R₁₂, R₁₃, and R₁₄; wherein R₁₁ is selected from the group consisting ofC₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆dialkylamino, halogen, heterocyclic, heterocyclic-oxy,heterocyclic-carbonyl, heteroaryl, and sulfonamide, and wherein C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylsulfonamide, alkylsulfonyl, C₁₋₄ alkylthio, carbamimidoyl, C₂₋₆dialkylamino, heterocyclic, heterocyclic-carbonyl, and heteroaryl areeach optionally substituted with 1 to 5 substituents selectedindependently from the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy,C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆ dialkylcarboxamide,heteroaryl, heterocyclic, hydroxyl, phenyl, and phosphonooxy whereinsaid C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, and R₁₄ are each independentlyselected form the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino,carbamimidoyl, carboxamide, cyano, C₂₋₆ dialkylamino, and halogen.

In some embodiments, Ar₁ is pyridyl optionally substituted with R₁₁,R₁₂, R₁₃, and R₁₄; wherein R₁₁ is selected from the group consisting ofC₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, C₂₋₆ dialkylamino, halogen,heterocyclic, and sulfonamide, and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, alkylsulfonyl, C₁₋₄ alkylthio, C₂₋₆ dialkylamino, andheterocyclic are each optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₄ alkylsulfonyl, C₃₋₇ cycloalkyloxy,heteroaryl, hydroxyl, phenyl, and phosphonooxy; and R₁₂, R₁₃, and R₁₄are each independently selected form the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide, cyano, C₂₋₆ dialkylamino,and halogen.

In some embodiments, Ar₁ is pyridyl optionally substituted with R₁₁,R₁₂, R₁₃, and R₁₄; wherein R₁₁ is selected from the group consisting ofC₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, C₂₋₆ dialkylamino, halogen,heterocyclic, and sulfonamide, and wherein C₁₋₄alkoxy, C₁₋₈ alkyl,C₁₋₄alkylamino, alkylsulfonyl, C₁₋₄ alkylthio, C₂₋₆ dialkylamino, andheterocyclic are each optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₄ alkylsulfonyl, C₃₋₇ cycloalkyloxy,heteroaryl, hydroxyl, phenyl, and phosphonooxy; and R₁₂, R₁₃, and R₁₄are each independently selected form the group consisting of C₁₋₈ alkyl,and halogen.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is heteroaryl. In some embodiments, theheteroaryl is optionally substituted with R₁₁. In some embodiments, R₁₁is selected from the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carboxamide, C₃₋₇cycloalkyl, halogen and sulfonamide. In some embodiments, R₁₁ isselected from the group consisting of C(O)CH₃, C(O)CH₂CH₃,C(O)CH₂CH₂CH₃, C(O)CH(CH₃)₂, C(O)CH₂CH₂CH₂CH₃, OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH(CH₃)(CH₂CH₃), CH₂(CH₂)₂CH₃, CH₂(CH₂)₃, CH₂(CH₂)₄CH₃, CH₂(CH₂)₅CH₃,C(O)NHCH₃, C(O)NHCH₂CH₃, C(O)NHCH₂CH₂CH₃, C(O)NHCH(CH₃)₂,C(O)NHCH₂(CH₂)₂CH₃, CCH, S(O)₂NHCH₃, S(O)₂NHCH₂CH₃, S(O)₂NHCH₂CH₂CH₃,S(O)₂NHCH(CH₃)₂, S(O)₂NHCH₂(CH₂)₂CH₃, S(O)₂NHCH(CH₃)CH₂CH₃, S(O)CH₃,S(O)CH₂CH₃, S(O)CH₂CH₂CH₃, S(O)CH(CH₃)₂, S(O)CH₂(CH₂)₂CH₃,S(O)CH(CH₃)CH₂CH₃, S(O)₂CH₃, S(O)₂CH₂CH₃, S(O)₂CH₂CH₂CH₃, S(O)₂CH(CH₃)₂,S(O)₂CH₂(CH₂)₂CH₃, S(O)₂CH(CH₃)CH₂CH₃, SCH₃, SCH₂CH₃, SCH₂CH₂CH₃,SCH(CH₃)₂ and SCH₂(CH₂)₂CH₃. In some embodiments, R₁₁ is selected fromthe group consisting of amino, arylsulfonyl, carboxy, cyano, C₃₋₇cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl and C₁₋₄haloalkylthio. In some embodiments, R₁₁ is selected from the groupconsisting of phenylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, Cl, F, Br, OCF₃, OCHF₂, OCH₂CF₃, CF₃, CHF₂, CH₂CF₃, SCF₃,SCHF₂ and SCH₂CF₃. In some embodiments, R₁₁ is selected from the groupconsisting of heterocyclic, heteroaryl, C₄₋₇ oxo-cycloalkyl, phenoxy andphenyl. In some embodiments, R₁₁ is selected from the group consistingof morpholin-4-yl, thiomorpholin-4-yl, 1-oxo-1λ⁴-thiomorpholin-4-yl,1,1-Dioxo-1λ⁶-thiomorpholin-4-yl, piperazin-1-yl,4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl,4-propyl-piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl,2,5-dioxo-imidazolidin-4-yl, 2,4-dioxo-thiazolidin-5-yl,4-oxo-2-thioxo-thiazolidin-5-yl, 3-methyl-2,5-dioxo-imidazolidin-4-yl,3-methyl-2,4-dioxo-thiazolidin-5-yl,3-methyl-4-oxo-2-thioxo-thiazolidin-5-yl,3-ethyl-2,5-dioxo-imidazolidin-4-yl, 3-ethyl-2,4-dioxo-thiazolidin-5-yl,and 3-ethyl-4-oxo-2-thioxo-thiazolidin-5-yl. In some embodiments, R₁₁ isselected from the group consisting of 1H-imidazol-4-yl,[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl, oxazol-5-yl,oxazol-2-yl, [1,3,4]oxadiazol-2-yl, [1,3,4]thiadiazol-2-yl,[1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl, tetrazol-1-yl,pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl,pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and[1,2,3]thiadiazol-4-yl. In some embodiments, R₁₁ is C₁₋₈ alkyl or C₁₋₄alkoxy, optionally substituted with 1 to 5 substituents selectedindependently from the group consisting of C₁₋₄ alkoxy, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,cyano, heterocyclic, hydroxyl and phenyl. In some embodiments, R₁₁ isC₁₋₄ alkylsulfonyl optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₄ alkoxy,carboxamide, heteroaryl, heterocyclic and phenyl. In some embodiments,the C₁₋₄ alkylsulfonyl is substituted with the heteroaryl group. In someembodiments, the heteroaryl is selected from the group consisting of1H-imidazol-4-yl, [1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl,[1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl,imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl,[1,3,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl,tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl,1,3-dioxo-1,3-dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl. In someembodiments, R₁₁ is arylsulfonyl, heteroaryl, phenoxy or phenyloptionally substituted with 1 to 5 substituents selected independentlyfrom the group consisting of C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carboxamide, carboxy, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio and hydroxyl. In some embodiments, R₁₁ isarylsulfonyl, heteroaryl, phenoxy or phenyl optionally substituted with1 to 5 substituents selected independently from the group consisting ofC₁₋₄ alkoxy, C₁₋₈ alkyl, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyland hydroxyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is heteroaryl. In some embodiments, theheteroaryl is optionally substituted with R₁₁. In some embodiments, R₁₁is of Formula (B):

wherein:

“p” and “r” are independently 0, 1, 2 or 3; and R₁₆ is H, C₁₋₅ acyl,C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl or phenyl, andwherein the heteroaryl or phenyl may be optionally substituted with 1 to5 substituents selected independently from the group consisting of C₁₋₄alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl. In someembodiments, p=0 and r=0. In some embodiments, R₁₆ is heteroaryl orphenyl optionally substituted with 1 to 5 substituents selectedindependently from the group consisting of C₁₋₄ alkoxy, amino, C₁₋₄alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl and hydroxyl. In some embodiments, the heteroaryl isselected from the group consisting of 1H-imidazol-4-yl,[1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl,pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl, oxazol-5-yl,oxazol-2-yl, [1,3,4]oxadiazol-2-yl, [1,3,4]thiadiazol-2-yl,[1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl, tetrazol-1-yl,pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl,pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and[1,2,3]thiadiazol-4-yl. In some embodiments, p=0 and r=1. In someembodiments, R₁₆ is carbo-C₁₋₆-alkoxy or carboxy. In some embodiments,p=2 and r=1. In some embodiments, R₁₆ is H, C₁₋₅ acyl or C₁₋₈ alkyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is heteroaryl. In some embodiments, theheteroaryl is optionally substituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅.In some embodiments, R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ are independentlyselected from the group consisting of H, C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, halogen, C₁₋₄ haloalkoxyand C₁₋₄ haloalkyl.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Ar₁ is heteroaryl. In some embodiments, theheteroaryl is optionally substituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅wherein two adjacent R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ groups together withthe atoms to which they are attached form a 5-, 6- or 7-memberedcycloalkyl, cycloalkenyl or heterocyclic group fused with Ar₁, whereinthe 5-, 6- or 7-membered group is optionally substituted with halogen.In some embodiments, the two adjacent groups form a 5-memberedheterocyclic group with the heteroaryl group. In some embodiments, thetwo adjacent groups form a 6-membered heterocyclic group with theheteroaryl group. In some embodiments, the two adjacent groups form a7-membered heterocyclic group with the heteroaryl group.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein R₄, R₅ and R₆ are independently H or CH₃.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein X is N.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein Y is N.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein X is N and Y is CH.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein X is CH and Y is N.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein X and Y are N.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein X and Y are CH.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein:

A and B are each independently —CH₂CH₂— or —CH₂—;

D is N—R₂;

V₁ is a bond;

V₂ is —CH₂—, —CH₂CH₂—, or a bond;

W and Q are each independently NH or O;

X and Y are each independently N or CH, provided that if either X or Yis CH then the other is N;

Z is selected from the group consisting of nitro, C₁₋₅ acyl, C₁₋₈ alkyl,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, amino, carbamimidoyl, cyano, C₃₋₇cycloalkyl, heterocyclic, and hydroxycarbamimidoyl, wherein saidheterocyclic is optionally substituted with a —CH₂NH₂ group;

R₂ is —C(O)OR₂₂, —C(O)R₂₂, —CH₂R₂₂, —R₂₂, —S(O)₂R₂₂, —CR₂₃R₂₄C(O)R₂₂, or—CR₂₃R₂₄C(O)NR₂₅R₂₂, wherein R₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl,heteroaryl, or heterocyclic each optionally substituted with 1 to 5substituents selected from the group consisting of C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl, phenyl and phenoxyare each optionally substituted with 1 to 5 substituents selected fromthe group consisting of amino, C₁₋₄ haloalkoxy, and heterocyclic; andR₂₃ and R₂₄ are each independently H or C₁₋₈ alkyl;

Ar₁ is aryl or heteroaryl each optionally substituted with R₁₁, R₁₂,R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the group consisting ofC₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, C₁₋₄alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide,carboxy, cyano, C₂₋₆ dialkylamino, halogen, heterocyclic,heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl, and sulfonamide,and wherein C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylsulfonamide, alkylsulfonyl, C₁₋₄ alkylthio,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,and heteroaryl are each optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, carboxy, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and

R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected form the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, carbamimidoyl, carboxamide, cyano,C₂₋₆ dialkylamino, and halogen.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein:

A and B are both —CH₂CH₂—;

D is N—R₂;

V₁ and V₂ are both a bond;

W and Q are each independently NH or O;

X and Y are both N;

Z is selected from the group consisting of nitro, C(O)CH₃, C(O)CH₂CH₃,CH₃, CH₂CH₃, CCH, NHS(O)₂CH₃, amino, carbamimidoyl, cyano, cyclopropyl,4,5-dihydro-1H-imidazol-2-yl, 5-aminomethyl-4,5-dihydro-oxazol-2-yl, andhydroxycarbamimidoyl;

R₂ is —C(O)OR₂₂, wherein R₂₂ is C₁₋₈ alkyl, or C₃₋₇ cycloalkyl eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfonyl, amino,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, halogen, and hydroxyl;

Ar₁ is phenyl optionally substituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅;

wherein R₁₁ is selected from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆dialkylamino, halogen, heterocyclic, heterocyclic-oxy,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and sulfonamide,and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and

R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected form the groupconsisting of C₁₋₈ alkyl, and halogen.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein:

A and B are both —CH₂CH₂—;

D is N—R₂;

V₁ and V₂ are both a bond;

W is NH;

Q is O;

X and Y are both N;

Z is nitro, cyano, C(O)CH₃, amino, CH₃, CH₂CH₃, or CCH;

R₂ is —C(O)OR₂₂, —C(O)R₂₂, —R₂₂, or —S(O)₂R₂₂ wherein R₂₂ is C₁₋₈ alkyl,C₃₋₇ cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl,amino, carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl,heterocyclic, hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein saidC₁₋₇ alkyl, phenyl and phenoxy are each optionally substituted with 1 to5 substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic;

Ar₁ is phenyl, 3-pyridyl, or 2-pyridyl each optionally substituted withR₁₁, R₁₂, R₁₃, R₁₄, and R₁₅,

wherein R₁₁ is selected from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆dialkylamino, halogen, heterocyclic, heterocyclic-oxy,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and sulfonamide,and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and

R₁₂, R₁₃, R₁₄, and R₁₅ are each independently CH₃, or F.

Some embodiments of the present invention pertain to compounds ofFormula (I) wherein:

A and B are both —CH₂CH₂—;

D is N—R₂;

V₁ and V₂ are both a bond;

W and Q are both O;

X and Y are both N;

Z is selected from the group consisting of CH₃, CH₂CH₃, cyclopropyl, orCCH;

R₂ is —C(O)OR₂₂, —C(O)R₂₂, —R₂₂, —CH₂C(O)R₂₂, or —CH₂C(O)NHR₂₂, whereinR₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, or heterocycliceach optionally substituted with 1 to 5 substituents selected from thegroup consisting of C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino,carboxy, cyano, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,halogen, heteroaryl, hydroxyl, phenyl, and phenoxy, wherein said C₁₋₇alkyl, is optionally substituted with 1 or 2 substituents selected fromthe group consisting of C₁₋₄ haloalkoxy, and heterocyclic;

Ar₁ is phenyl, 2-pyridyl, or 3-pyridyl each optionally substituted withR₁₁, R₁₂, R₁₃, R₁₄, and R₁₅,

wherein R₁₁ is selected from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl C₁₋₄ alkylamino,C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino,carbamimidoyl, carboxy, cyano, C₂₋₆ dialkylamino, halogen, heterocyclic,heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl, and sulfonamide,and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₂₋₆ dialkylamino,and heteroaryl are each optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₄ alkoxy, C₁₋₇alkyl, C₁₋₄ alkylcarboxamide, heteroaryl, hydroxyl, and phosphonooxywherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₄ alkoxy and hydroxy; and

R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected form the groupconsisting of C₁₋₈ alkyl, and halogen.

In some embodiments, compounds of the present invention are when R₁₁ isselected from the group consisting of:

-   sulfamoyl [—S(O)₂NH₂],-   acetylsulfamoyl [—S(O)₂NHC(O)CH₃],-   propionylsulfamoyl [—S(O)₂NHC(O)CH₂CH₃],-   butyrylsulfamoyl [—S(O)₂NHC(O)CH₂CH₂CH₃],-   pentanoylsulfamoyl [—S(O)₂NHC(O)CH₂CH₂CH₂CH₃],-   methanesulfonyl [—S(O)₂CH₃],-   ethanesulfonyl [—S(O)₂CH₂CH₃],-   propane-1-sulfonyl [—S(O)₂CH₂CH₂CH₃],-   hydroxymethyl (—CH₂OH);-   2-hydroxyethyl (—CH₂CH₂OH);-   3-hydroxypropyl (—CH₂CH₂CH₂OH);-   4-hydroxy-butyl (—CH₂CH₂CH₂CH₂OH);-   phosphonooxymethyl [—CH₂OP(O)(OH)₂];-   2-phosphonooxy-ethyl [—CH₂CH₂OP(O)(OH)₂];-   3-phosphonooxy-propyl [—CH₂CH₂CH₂OP(O)(OH)₂]; and-   4-phosphonooxy-butyl [—CH₂CH₂CH₂CH₂OP(O)(OH)₂].

In some embodiments, R₁₁ is methoxy, ethoxy, isobutoxy or3-methyl-butoxy. In some embodiments, R₁₁ is pyridyl optionallysubstituted with C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, halogen orhydroxyl.

In some embodiments, R₁₁ is 2-pyridyl optionally substituted with C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, halogen or hydroxyl.

In some embodiments, R₁₁ is 3-pyridyl optionally substituted with C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, halogen or hydroxyl.

Some embodiments of the present invention include one of more of thecompounds illustrated in TABLES A, B, C, D and E; these TABLES are shownbelow.

TABLE A Cmpd # Structure Chemical Name A1

4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4yloxy]-piperidine-1-carboxylic acid tert-butyl ester A2

(4-Methanesulfonyl-phenyl)-[5- nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine A3

1-{4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3- dimethyl-butan-1-one A4

(4-Methanesulfonyl-phenyl)-[5- nitro-6-(1-thiophen-3-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]- thiophen-3-ylmethyl-amine A5

(4-Methanesulfonyl-phenyl)-[5- nitro-6-(1-pyridin-2-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]- amine A6

(4-Methanesulfonyl-phenyl)-[5- nitro-6-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]- amine A7

{6-[1-(3,3-Dimethyl-butyl)- piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine A8

(4-Methanesulfonyl-phenyl)-{6-[1- (3-methyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}- amine A9

(4-Methanesulfonyl-phenyl)-[5- nitro-6-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy)- pyrimidin-4-yl]-amine A10

4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid ethyl ester A11

1-{4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3- dimethyl-butan-2-one A12

{6-[1-(2-Ethoxy-ethyl)-piperidin-4- yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine A13

4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-piperidine-1- carboxylic acid tert-butyl ester A14

4-{2-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-ethyl}-piperidine-1- carboxylic acid tert-butyl ester A15

3-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester A16

3-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1- carboxylic acid tert-butyl ester A17

3-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1- carboxylic acid tert-butyl ester A18

4-[5-Cyano-6-(6-methylsulfanyl- pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester A19

4-[5-Cyano-6-(6-methanesulfonyl- pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester A20

[6-(1-Hexyl-piperidin-4-yloxy)-5- nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine A21

[6-(1-Cyclopropylmethyl-piperidin- 4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine A22

4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A23

4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid 2-isopropyl-5-methyl-cyclohexylester A24

{4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-3-yl- methanone A25

(2-Chloro-pyridin-3-yl)-{4-[6-(4- methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin- 1-yl}-methanone A26

{4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-2-yl- methanone A27

(4-Methanesulfonyl-phenyl)-[6-(1- methanesulfonyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]- amine A28

(4-Methanesulfonyl-phenyl)-{5- nitro-6-[1-(propane-1-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}- amine A29

{6-[1-(Butane-1-sulfonyl)- piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine A30

(4-Methanesulfonyl-phenyl)-{5- nitro-6-[1-(thiophene-2-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}- amine A31

(4-Methanesulfonyl-phenyl)-{6-[1- (1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yloxy]-5- nitro-pyrimidin-4-yl}-amine A32

{6-[1-(2,4-Dimethyl-thiazole-5- sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine A33

4-[5-Cyano-6-(3-fluoro-4- methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid tert-butyl ester A34

4-[6-(2-Fluoro-4-methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester A35

4-[5-Cyano-6-(4-methanesulfonyl- phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert- butyl ester A36

4-[6-(6-Methanesulfonyl-pyridin-3- ylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester A37

4-[5-Acetyl-6-(6-methanesulfonyl- pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester A38

4-[5-Amino-6-(2-fluoro-4- methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid tert-butyl ester A39

4-[5-Cyano-6-(4-methanesulfonyl- phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A40

4-[5-Cyano-6-(4-methanesulfonyl- phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid ethyl ester A41

4-[5-Cyano-6-(4-methanesulfonyl- phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isobutyl ester A42

4-(4-Methanesulfonyl- phenylamino)-6-[1-(tetrahydro-furan-2-carbonyl)-piperidin-4- yloxy]-pyrimidine-5-carbonitrile A43

4-[1-(3,3-Dimethyl-2-oxo-butyl)- piperidin-4-yloxy]-6-(4-methanesulfonyl-phenylamino)- pyrimidine-5-carbonitrile A44

4-(4-Methanesulfonyl- phenylamino)-6-[1-(pyridine-3-carbonyl)-piperidin-4-yloxy]- pyrimidine-5-carbonitrile A45

4-(1-Formyl-piperidin-4-yloxy)-6- (4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile A46

4-(4-Methanesulfonyl- phenylamino)-6-[1-(pyridine-2-carbonyl)-piperidin-4-yloxy]- pyrimidine-5-carbonitrile A47

4-[6-(4-Cyano-2-fluoro- phenylamino)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A48

4-[5-Ethynyl-6-(2-fluoro-4- [1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A49

4-{5-Ethynyl-6-[1-(3-isopropyl [1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-ylamino}-3- fluoro-benzonitrile A50

{5-Ethynyl-6-[1-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-(2-fluoro-4- methanesulfonyl-phenyl)-amine A51

4-{6-[2,5-Difluoro-4-(2- methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin- 4-yloxy}-piperidine-1-carboxylic acidisopropyl ester A52

4-{6-[2-Fluoro-4-(2-sulfamoyl- ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A53

4-{6-[6-(2-Fluoro-ethyl)-2-methyl- pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A54

4-{2-[4-Fluoro-6-(2-isopropoxy- ethyl)-pyridin-3-ylamino]-3-methyl-pyridin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A55

4-{6-[2,5-Difluoro-4-(2- [1,2,4]triazol-1-yl-ethyl)-phenylamino]-5-methyl-pyrimidin- 4-yloxy}-piperidine-1-carboxylic acidisopropyl ester A56

4-{5-Ethynyl-6-[2-fluoro-4-(4- methoxy-pyridin-2-yl)-phenylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester A57

4-{6-[2-Fluoro-4-(2- propionylsulfamoyl-ethyl)-phenylamino]-5-methyl-pyrimidin- 4-yloxy}-piperidine-1-carboxylic acidisopropyl ester A58

4-{6-[2-Fluoro-4-(2- methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin- 4-yloxy}-piperidine-1-carboxylic acidisopropyl ester A59

4-{6-[2,3-Difluoro-4-(2- methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin- 4-yloxy}-piperidine-1-carboxylic acidisopropyl ester A60

4-[5-Acetyl-6-(6-methanesulfonyl- pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isobutyl ester A61

1-[4-(1-Benzyl-azetidin-3-yloxy)-6- (6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone A62

4-[5-Cyano-6-(6-propylamino- pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A63

4-[5-Cyano-6-(2-fluoro-4- isopropylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A64

4-[5-Cyano-6-(2-fluoro-4- propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A65

4-[5-Cyano-6-(2-fluoro-4-propoxy- phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A66

4-[5-Cyano-6-(6-propyl-pyridin-3- ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A67

4-{5-Cyano-6-[4-(2- dimethylamino-ethylsulfanyl)-2-fluoro-phenylamino]-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester A68

4-{5-Cyano-6-[4-(2- dimethylamino-ethanesulfonyl)-2-fluoro-phenylamino]-3-oxy- pyrimidin-4-yloxy}-piperidine-1- carboxylicacid isopropyl ester A69

4-{5-Cyano-6-[2-fluoro-4-(4- methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester A70

4-{5-Cyano-6-[2-fluoro-4-(3- methyl-butylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A71

4-[5-Cyano-6-(2-fluoro-4- morpholin-4-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A72

4-{5-Cyano-6-[4-(2- dimethylamino-ethylamino)-2-fluoro-phenylamino]-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester A73

4-[5-Cyano-6-(4-dimethylamino-2- fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A74

4-{5-Cyano-6-[2-fluoro-4-(2- pyrrolidin-1-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester A75

4-[6-(2-Fluoro-4-methanesulfonyl- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A76

4-{5-Cyano-6-[2-fluoro-4-(2- morpholin-4-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester A77

4-[6-(2-Fluoro-4-iodo- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A78

4-[5-Cyano-6-(2-fluoro-4- methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A79

4-[6-(2-Fluoro-4-morpholin-4-yl- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A80

4-[6-(2,5-Difluoro-4-propoxy- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A81

4-[6-(2-Fluoro-4-propylamino- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A82

4-{6-[2-Fluoro-4-(2-methoxy- ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterA83

4-(6-{2-Fluoro-4-[(tetrahydro- furan-2-ylmethyl)-amino]-phenylamino}-5-methyl-pyrimidin- 4-yloxy)-piperidine-1-carboxylic acidisopropyl ester A84

4-{6-[2-Fluoro-4-(2- methanesulfonyl-ethylamino)-phenylamino]-5-methyl-pyrimidin- 4-yloxy}-piperidine-1-carboxylic acidisopropyl ester A85

4-(6-{2-Fluoro-4-[(2- methanesulfonyl-ethyl)-methyl-amino]-phenylamino}-5-methyl- pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester A86

4-[6-(4-Bromo-2,5-difluoro- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A87

4-[6-(4-Cyano-2-fluoro- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A88

4-[6-(4-Cyano-2,5-difluoro- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A89

4-[6-(2,5-Difluoro-4-morpholin-4- yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A90

4-[6-(6-Chloro-2-methyl-pyridin-3- ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A91

4-[5-Methyl-6-(2-methyl-6- morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A92

4-[5-(4,5-Dihydro-1H-imidazol-2- yl)-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropylester A93

(2-Fluoro-4-methanesulfonyl- phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-5-methyl-pyrimidin-4-yl}-amine A94

4-[6-(2-Fluoro-4-propoxy- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A95

4-{6-[2-Fluoro-4-(2- methanesulfonyl-ethoxy)-phenylamino]-5-methyl-pyrimidin- 4-yloxy]-piperidine-1-carboxylic acidisopropyl ester A96

4-{6-[2-Fluoro-4-(2-methoxy- ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A97

4-{6-[2-Fluoro-4-(2-isopropoxy- ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A98

4-[6-(6-Chloro-4-methyl-pyridin-3- ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A99

4-[6-(2-Fluoro-4-methanesulfonyl- phenylamino)-5-(N-hydroxycarbamimidoyl)-pyrimidin- 4-yloxy]-piperidine-1-carboxylic acidisopropyl ester A100

4-[5-Carbamimidoyl-6-(2-fluoro-4- methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A101

4-{6-[2-Fluoro-4-(tetrahydro-furan- 2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterA102

4-[5-Methyl-6-(4-methyl-6- morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A103

4-{6-[6-(2-Methoxy-ethoxy)-2- methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterA104

4-{6-[6-(2-Methoxy-ethoxy)-4- methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterA105

4-{6-[2,5-Difluoro-4-(2-methoxy- ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A106

4-{6-[2-Fluoro-4-(2-isopropoxy- ethylsulfamoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterA107

4-{6-[2,5-Difluoro-4-(N- hydroxycarbamimidoyl)-phenylamino]-5-methyl-pyrimidin- 4-yloxy}-piperidine-1-carboxylic acidisopropyl ester A108

4-[6-(4-Carbamoyl-2,5-difluoro- phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A109

4-{6-[(2-Fluoro-4-methanesulfonyl- phenyl)-(2-methoxy-ethyl)-amino]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester A110

4-[6-(4-Carbamimidoyl-2,5- difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester A111

4-{6-[4-(2-Ethoxy-ethoxy)-2- fluoro-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A112

4-{6-[2-Fluoro-4-(tetrahydro-pyran- 4-yloxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A113

4-{6-[2-Fluoro-4-(2-hydroxy- ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester A114

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-butan-1-one A115

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-pentan-1-one A116

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-methyl-butan-1- one A117

4-{6-[2-Fluoro-4-(pyridin-2- ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterA118

4-[2-(2-Fluoro-4-methanesulfonyl- phenylamino)-3-methyl-pyridin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A119

4-[6-(6-Chloro-4-fluoro-pyridin-3- ylamino)-5-cyano-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester A120

4-[5-Amino-6-(2-fluoro-4- methanesulfonyl-phenylamino)-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester

TABLE B Cmpd # Structure Chemical Name B1

4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester B2

N-(4-Methanesulfonyl-phenyl)-5- nitro-N′-piperidin-4-yl-pyrimidine-4,6-diamine B3

1-{4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-ethanone B4

1-{4-[6-(4-Methanesulfonyl- phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-2,2- dimethyl-propan-1-one B5

4-({[6-(2-Fluoro-4- methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yl]-isopropyl- amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester

TABLE C Cmpd # Structure Chemical Name C1

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-6-[1-(3-methoxy-propyl)-piperidin-4-yloxy]-5-methyl- pyrimidine C2

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-methoxy-propan- 2-ol C3

4-[6-(2-Fluoro-4-morpholin-4-yl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C4

{4-[6-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-[6-(2- pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-methanone C5

(6-Amino-pyridin-3-yl)-{4-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-methanone C6

4-[5-Ethyl-6-(2-fluoro-4- methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C7

4-{6-[2-Fluoro-4-(5- isopropoxymethyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-5-methyl-pyrimidin- 4-yloxy}-piperidine-1-carboxylic acidisopropyl ester C8

4-{6-[2-Fluoro-4-(5-methoxy- pyridin-2-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C9

4-[6-(2-Fluoro-phenoxy)-5-methyl- pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C10

4-{6-[6-(2-Isopropoxy-ethylamino)- 2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC11

4-{6-[6-(2-Cyclopropoxy- ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester C12

4-{6-[6-(2-Hydroxy-ethylsulfanyl)- 2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC13

4-{6-[2-Fluoro-4-(pyridine-2- carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C14

4-[6-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methanesulfonylamino-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C15

4-[5-Methyl-6-(2-methyl-6-pentyl- pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C16

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(3-fluoro-phenyl)- ethanoneC17

4-[6-(4-Methoxy-6′-methyl-3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′-yloxy)-5-methyl-pyrimidin-4- yloxy]-piperidine-1-carboxylic acidisopropyl ester C18

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-6-[1-(2-pyridin-3-yl-ethyl)-piperidin-4-yloxy]- pyrimidine C19

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-2-(4-trifluoromethoxy-phenoxy)-propan- 1-one C20

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-2-(4-trifluoromethoxy-phenoxy)- ethanone C21

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone C22

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-pyridin-2-yl- ethanone C23

N-(4-Chloro-phenyl)-2-{4-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-acetamide C24

4-{6-[6-(2-Methoxy- ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester C25

N-(3-Chloro-phenyl)-2-{4-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-acetamide C26

N-(3,5-Dichloro-phenyl)-2-{4-[6- (2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-acetamide C27

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-5-methyl-pyrimidine C28

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-N-(4-trifluoromethyl-phenyl)-acetamide C29

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-N-phenyl-acetamide C30

2-{4-6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-N-(4-isopropyl-phenyl)-acetamide C31

4-(6-{2-Fluoro-4-[(2-hydroxy- ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)- piperidine-1-carboxylic acid isopropylester C32

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-N-(4-methoxy-phenyl)-acetamide C33

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-N-(3-trifluoromethyl-phenyl)-acetamide C34

4-[6-(5-Iodo-pyridin-2-yloxy)-5- methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C35

4-{6-[2-Fluoro-4-(3-methoxy- propane-1-sulfonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC36

4-(6-{2-Fluoro-4-[N-(2-isopropoxy- ethyl)-carbamimidoyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)- piperidine-1-carboxylic acid isopropyl esterC37

4-{6-[6-(2-Isopropoxy-ethyl)-2- methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C38

4-[6-(4-Carboxy-2-fluoro- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C39

4-{5-Methyl-6-[2-methyl-6-(2- pyridin-2-yl-ethoxy)-pyridin-3-yloxy]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC40

4-(4-Bromo-2-fluoro-phenoxy)-6- [1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl- pyrimidine C41

4-{6-[2-Fluoro-4-(thiophene-2- carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C42

4-[6-(5-Methanesulfonyl-pyridin-2- yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C43

4-{6-[6-(2-Hydroxy-ethylamino)-2- methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C44

4-[5-Cyclopropyl-6-(2-fluoro-4- methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C45

4-(6-{6-[(2-Isopropoxy-ethyl)- methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C46

4-{6-[6-(2-Methanesulfonyl- ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester C47

4-{6-[6-(2-Isopropoxy- ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester C48

4-{6-[6-(2-Hydroxy- ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester C49

4-[6-(6-Amino-2-methyl-pyridin-3- yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C50

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-6-[1-(3-methyl-butyl)-piperidin-4-yloxy]- pyrimidine C51

4-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy}- piperidin-1-yl}-4-oxo-butyric acid C52

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-morpholin-4-yl- ethanoneC53

1-(3,4-Dichloro-phenyl)-2-{4-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C54

1-(3-Chloro-phenyl)-2-{4-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C55

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanone C56

4-{6-[6-(2-Methoxy-ethylsulfanyl)- 2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC57

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-thiophen-3-yl- ethanone C58

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-phenyl-ethanone C59

1-(2,4-Dimethoxy-phenyl)-2-{4-[6- (2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C60

1-(2,5-Dimethoxy-phenyl)-2-{4-[6- (2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C61

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-pyridin-2-yl- ethanone C62

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-6-[1-(4-methyl-pentyl)-piperidin-4-yloxy]- pyrimidine C63

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-isopropoxy- propan-1-oneC64

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-4-isopropoxy-butan- 1-one C65

4-[6-(6-Chloro-2-methyl-pyridin-3- yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C66

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-hydroxy-propan- 1-one C67

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(4-fluoro-phenyl)- ethanoneC68

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(4-trifluoromethyl-phenyl)-ethanone C69

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(5-pyridin-2-yl-thiophen-2-yl)-ethanone C70

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-6-[1-(5-methyl-hexyl)-piperidin-4-yloxy]- pyrimidine C71

3-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-oxo-propane-1- sulfonicacid C72

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-thiophen-2-yl- ethanone C73

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-6-(1-pentyl-piperidin-4-yloxy)-pyrimidine C74

4-(1-Butyl-piperidin-4-yloxy)-6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidine C75

4-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}- cyclohexanecarboxylic acidC76

1-(4-Diethylamino-phenyl)-2-{4-[6- (2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C77

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(2-methyl-4-phenyl-furan-3-yl)-ethanone C78

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3,3-dimethyl-butan- 2-one C79

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-6-(1-hexyl-piperidin-4-yloxy)-5-methyl-pyrimidine C80

4-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-butyric acid C81

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-pentan-2-one C82

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-hexan-2-one C83

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-heptan-2-one C84

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-4-methyl-pentan-2- one C85

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-5-methyl-hexan-2- one C86

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-6-methyl-heptan-2- one C87

5-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-4-oxo-pentanoic acid C88

5-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-4-oxo-pentanenitrile C89

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-2-pyridin-2-yl- ethanone C90

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-pyridin-4-yl- ethanone C91

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-pyridin-3-yl- ethanone C92

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-ylmethyl}-acrylic acid C93

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-butan-2-one C94

1-[1,4]Dioxan-2-yl-2-{4-[6-(2 fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C95

1-(2,3-Dihydro-[1,4]dioxin-2-yl)-2- {4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C96

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-p-tolyl-ethanone C97

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(4-methoxy-phenyl)-ethanone C98

1-(2-Chloro-phenyl)-2-{4-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C99

3-(2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-acetyl)-benzonitrile C100

1-(2,4-Dimethyl-phenyl)-2-{4-[6- (2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C101

4-(6-{2-Fluoro-4-[(2-isopropoxy- ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)- piperidine-1-carboxylic acid isopropylester C102

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(4-methanesulfonyl-phenyl)-ethanone C103

1-(4-Chloro-3-methyl-phenyl)-2-{4- [6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C104

1-(4-Difluoromethoxy-phenyl)-2- {4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C105

1-(4-Chloro-phenyl)-2-{4-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C106

4-(2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-acetyl)-benzonitrile C107

1-(3,4-Difluoro-phenyl)-2-{4-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4- yloxy]-piperidin-1-yl}-ethanone C108

1-(2,3-Dihydro-benzo[1,4]dioxin-6- yl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5- methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone C109

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-(5-phenyl-thiophen-2-yl)-ethanone C110

2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-thiophen-2-yl- ethanoneC111

{4-[6-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetic acid ethyl ester C112

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-methoxy-propan- 2-ol C113

4-{6-[2-Fluoro-4-(2-isopropoxy- ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC114

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-6-[1-(4-methoxy-cyclohexyl)-piperidin-4-yloxy]-5- methyl-pyrimidine C115

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-butan-1-one C116

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-pentan-1-one C117

4-[6-(2,4-Difluoro-phenoxy)-5- methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C118

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-hexan-1-one C119

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-methyl-butan-1- one C120

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-4-methyl-pentan-1- one C121

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-5-methyl-hexan-1- one C122

4-{6-[2-Fluoro-4-(2-methoxy- ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy} - piperidine-1-carboxylic acid isopropyl esterC123

4-{6-[2-Fluoro-4-(2-isobutoxy- ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C124

4-{6-[4-(2-Cyclopropoxy-ethoxy)- 2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C125

4-{6-[4-(2-Ethoxy-ethoxy)-2- fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C126

4-{6-[2-Fluoro-4-(3-methoxy- propoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C127

4-[6-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C128

4-{6-[2-Fluoro-4-(2-pyridin-2-yl- ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C129

4-{6-[2-Fluoro-4-(tetrahydro-pyran- 4-yloxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C130

4-[6-(4-Bromo-2-fluoro-phenoxy)- 5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C131

4-{6-[4-(2-tert-Butoxy-ethoxy)-2- fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C132

4-{6-[2-Fluoro-4-(methoxy-methyl carbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C133

1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-methoxy-propan- 1-one C134

4-[6-(4-Cyano-2-fluoro-phenoxy)- 5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C135

4-[5-(5-Aminomethyl-4,5-dihydro- oxazol-2-yl)-6-(2-fluoro-4-methanesulfonyl-phenoxy)- pyrimidin-4-yloxy]-piperidine-1- carboxylicacid isopropyl ester C136

4-{6-[6-(2-Methoxy-ethylamino)-2- methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C137

4-{6-[6-(3-Methanesulfonyl- pyrrolidin-1-yl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester C138

4-[6-(6-Benzylamino-2-methyl- pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C139

4-[6-(4-Carbamoyl-2-fluoro- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C140

4-{6-[2-Fluoro-4-(2-isopropoxy- ethylamino)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C141

4-(6-{2-Fluoro-4-[(tetrahydro- furan-2-ylmethyl)-amino]-phenoxy}-5-methyl-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C142

4-(6-{6-[(2-Methanesulfonyl-ethyl)- methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C143

4-[6-(2-Fluoro-4- hydroxycarbamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropyl esterC144

4-{6-[2-Fluoro-4-(2-pyrrolidin-1-yl- ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC145

4-{6-[2-Fluoro-4-(4-isopropyl- piperazine-1-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC146

4-{6-[2-Fluoro-4-(2-morpholin-4- yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C147

4-{6-[2-Fluoro-4-(2- methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC148

4-{6-[2-Fluoro-4-(2-hydroxy- ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C149

4-[6-(4-Carboxymethyl-2-fluoro- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C150

4-[6-(4-Dimethylcarbamoylmethyl- 2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C151

4-[6-(2-Fluoro-4-sulfamoyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C152

4-[6-(2-Fluoro-4- propionylsulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropyl esterC153

4-[5-Ethynyl-6-(2-fluoro-4- methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C154

4-{6-[2-Fluoro-4-(2-phosphonooxy- ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C155

4-[5-Bromo-6-(2-fluoro-4- methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C156

4-(6-{2-Fluoro-4-[2-(2- methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl- pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester C157

4-[6-(4-Carbamoylmethyl-2-fluoro- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C158

4-[6-(2-Fluoro-4-{[(tetrahydro- furan-2-ylmethyl)-carbamoyl]-methyl}-phenoxy)-5-methyl- pyrimidin-4-yloxy]-piperidine-1- carboxylicacid isopropyl ester C159

4-[6-(2-Fluoro-3-sulfamoyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C160

C-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-C-(4-fluoro-phenyl)-methyleneamine C161

3-tert-Butoxy-1-{4-[6-(2-fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-propan-1-one C162

4-[6-(2-Fluoro-4-sulfo-phenoxy)-5- methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C163

2-Ethoxy-1-{4-[6-(2-fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-ethanone C164

{4-[6-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-(tetrahydro- furan-2-yl)-methanone C165

(S)-1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one C166

4-(6-{2-Fluoro-4-[2-(3-hydroxy- piperidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C167

4-{6-[2-Fluoro-4-(2-morpholin-4- yl-2-oxo-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C168

4-{6-[2-Fluoro-4-(2-imidazol-1-yl- ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C169

4-{6-[2-Fluoro-4-(2-[1,2,3]triazol- 1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C170

(R)-1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one C171

(S)-1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-hydroxy-butan-1- one C172

(R)-N-(1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidine-1-carbonyl}-2-methyl-propyl)-acetamide C173

(S)-N-(1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidine-1-carbonyl}-2-methyl-propyl)-acetamide C174

(R)-N-(2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy}- piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide C175

(S)-N-(2-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide C176

4-[6-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid (S)-tetrahydro-furan-3-yl ester C177

4-[6-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid (R)-tetrahydro-furan-3-yl ester C178

4-[6-(2-Amino-4-ethanesulfonyl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C179

4-[6-(4-Methanesulfonyl-phenoxy)- 5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C180

(1-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidine-1-carbonyl}-2-methyl-propyl)-carbamic acid tert-butyl ester C181

4-{6-[2-Fluoro-4-(6-methoxy- pyridin-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C182

3-Amino-1-{4-[6-(2-fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-4-methyl-pentan-1- one C183

2-Amino-1-{4-[6-(2-fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidin-1-yl}-3-methyl-butan-1- one C184

4-{6-[2-Fluoro-4-(2-isopropoxy- ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C185

4-[5-Methyl-6-(4-sulfo-phenoxy)- pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C186

4-[6-(2,5-Difluoro-4- trifluoromethoxy-phenoxy)-5-ethynyl-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropyl esterC187

4-[6-(2,5-Difluoro-4- trifluoromethoxy-phenoxy)-5-prop-1-ynyl-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropyl esterC188

4-[5-Ethynyl-6-(2-fluoro-4- methoxy-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C189

4-[5-Ethynyl-6-(6-methoxy-4- methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C190

4-{5-Ethynyl-6-[6-(2-isopropoxy- ethyl)-2-methyl-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C191

4-[6-(4-Cyano-2-fluoro-phenoxy)- 5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C192

4-[5-Ethynyl-6-(2-fluoro-4- [1,2,4]triazol-4-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C193

4-[5-Ethynyl-6-(2-fluoro-4- [1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C194

1-{4-[5-Ethynyl-6-(2-fluoro-4- [1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yloxy]-piperidin-1-yl}- 3-pyridin-2-yl-propan-1-one C195

4-{5-Ethynyl-6-[1-(3-isopropyl [1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yloxy}-3- fluoro-benzonitrile C196

5-Ethynyl-4-(2-fluoro-4 methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)- piperidin-4-yloxy]-pyrimidine C197

4-[1-(3-Ethyl-[1,2,4]oxadiazol-5- yl)-piperidin-4-yloxy]-5-ethynyl-6-(2-fluoro-4-methanesulfonyl- phenoxy)-pyrimidine C198

4-[1-(3-Ethyl-[1,2,4]oxadiazol-5- yl)-piperidin-4-yloxy]-6-(2-fluoro-4-methanesulfonyl-phenoxy)-5- methyl-pyrimidine C199

4-(2-Fluoro-4-methanesulfonyl- phenoxy)-5-methyl-6-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-pyrimidine C200

4-[6-(2-Fluoro-4- methanesulfonylamino-phenoxy)-5-methyl-pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropyl esterC201

cis-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- cyclohexyl}-carbamic acid isopropyl esterC202

trans-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- cyclohexyl}-carbamic acid isopropyl esterC203

N-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- cyclohexyl}-3-methyl-butyramide C204

N-{4-[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]- cyclohexyl}-isobutyramide C205

4-{6-[2,5-Difluoro-4-(2- methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC206

4-{6-[4-Fluoro-6-(2- methanesulfonyl-ethyl)-pyridin-3-yloxy]-5-methyl-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester C207

4-{5-Cyclopropyl-6-[2,5-difluoro-4- (2-hydroxy-ethyl)-phenoxy]-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C208

4-(5-Cyclopropyl-6-{2,5-difluoro-4- [2-(4-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C209

4-{6-[2,5-Difluoro-4-(2-morpholin- 4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C210

4-(6-{2-Fluoro-4-[2-(4-methoxy- piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)- piperidine-1-carboxylic acid isopropyl esterC211

4-{6-[6-(2-Fluoro-ethyl)-2-methyl- pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C212

4-{6-[2-Fluoro-4-(1-hydroxy- cyclopropylmethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC213

4-{2-[2,5-Difluoro-4-(2- methanesulfonyl-ethyl)-phenoxy]-3-methyl-pyridin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC214

(R)-4-(6-{2-Fluoro-4-[2-(3- methoxy-piperidin-1-yl)-ethyl]-ethyl]-phenoxy}-5-methyl-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C215

(S)-4-(6-{2-Fluoro-4-[2-(3- methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C216

(R)-4-(5-Ethynyl-6-{2-fluoro-4-[2- (2-methoxy-piperidin-1-yl)-ethyl]-phenoxyl-pyrimidin-4-yloxy)- piperidine-1-carboxylic acid isopropylester C217

(S)-4-(2-{2-Fluoro-4-[2-(2- methoxy-piperidin-1-yl)-ethyl]-phenoxyl-3-methyl-pyridin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C218

4-{6-[4-Fluoro-6-(2-morpholin-4- yl-ethyl)-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC219

4-{5-Ethynyl-6-[4-fluoro-6-(2- methanesulfonyl-ethyl)-pyridin-3-yloxy]-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC220

4-{2-[2,5-Difluoro-4-(2- isopropoxy-ethyl)-phenoxy]-3-methyl-pyridin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC221

4-{6-[2-Fluoro-4-(2- propionylsulfamoyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4- yloxy}-piperidine-1-carboxylic acidisopropyl ester C222

4-{6-[2-Fluoro-4-(2-sulfamoyl- ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- acid isopropyl ester C223

4-{6-[2,5-Difluoro-4-(2-sulfamoyl- ethyl)-phenoxy]-5-ethynyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C224

4-{6-[2,5-Difluoro-4-(2- [1,2,4]triazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropylester C225

4-{6-[2,3-Difluoro-4-(2- methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC226

4-(2-{2-Fluoro-4-[2-(6-methoxy- pyridin-2-yl)-ethyl]-phenoxy}-3-methyl-pyridin-4-yloxy)-piperidine- 1-carboxylic acid isopropyl esterC227

4-(6-{2-Fluoro-4-[2-(3-methoxy- pyridin-2-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)- piperidine-1-carboxylic acid isopropyl esterC228

4-[6-(3-Fluoro-1-oxy-pyridin-4- yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C229

4-[6-(5′-Methoxy-6-methyl- [2,2′]bipyridinyl-5-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester C230

4-{5-Ethynyl-6-[2-fluoro-4-(4- methoxy-pyridin-2-yl)-phenoxy]-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C231

4-{6-[2-Fluoro-4-(3-methoxy- pyridin-2-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C232

4-(6-{2,5-Difluoro-4-[2-(3- methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C233

4-(6-{2,5-Difluoro-4-[2-(3- methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-ethynyl-pyrimidin-4- yloxy)-piperidine-1-carboxylic acidisopropyl ester C234

4-{6-[2-Fluoro-4-(5-methoxy- pyridin-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1- carboxylic acid isopropyl ester C235

4-[6-(2-Fluoro-4-pyridin-4-yl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C236

4-[6-(3-Fluoro-biphenyl-4-yloxy)-5- methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C237

4-[6-(2-Fluoro-4-pyridin-3-yl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C238

4-[6-(2-Fluoro-4-pyrimidin-5-yl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C239

4-[6-(2-Fluoro-4-thiophen-3-yl- phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C240

4-[6-(4-Ethynyl-2-fluoro-phenoxy)- 5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester C241

(R)-4-{6-[2-Fluoro-4-(2-oxo- oxazolidin-4-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl esterC242

(S)-4-{6-[2-Fluoro-4-(2-oxo- oxazolidin-4-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}- piperidine-1-carboxylic acid isopropyl ester

TABLE D Cmpd # Structure Chemical Name D1

4-({Cyclopropyl-[6-(2-fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}- methyl)-piperidine-1-carboxylic acidtert-butyl ester D2

4-({Cyclopropyl-[6-(2-fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}- methyl)-piperidine-1-carboxylic acidisopropyl ester D3

4-({[6-(2-Fluoro-4- methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-isopropyl- amino}-methyl)-piperidine-1-carboxylic acid isopropyl ester D4

4-({Cyclopropylmethyl-[6-(2- fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]- amino}-methyl)-piperidine-1-carboxylic acid isopropyl ester

TABLE E Cmpd # Structure Chemical Name E11

4-[6-(2-Fluoro-4-methanesulfonyl- phenylamino)-5-methyl-pyrimidin-4-ylsulfanyl]-piperidine-1- carboxylic acid isopropyl ester

Additionally, compounds of the present invention encompass allpharmaceutically acceptable salts, solvates, and particularly hydrates,thereof.

General Synthetic Methods

As a result of their profound biological significance in highereukaryotes and utilization of the pyrimidine core in a number ofmarketed drugs (Scheme 1) and other medicinally relevant compounds,pyrimidines and pyridines play pivotal roles as chemotypes in drugdiscovery campaigns. As a direct consequence of this there is a wealthof scientific literature describing synthetic construction, as well aschemical modification and elaboration of these classes of heterocycles.

The novel substituted pyrimidines and pyridines of the present inventioncan be prepared according to a variety of synthetic manipulations, allof which would be familiar to one skilled in the art of syntheticorganic chemistry. Certain methods for the preparation of compounds ofthe present invention include, but are not limited to, those describedin Schemes 2-13 set forth in this section of the specification and inthe Examples, infra.

Common dihalo-substituted intermediates 9.1 and 9.2, used as a startingpoint for the synthesis of compounds of the present invention arecommercially available or can be prepared by methods know in the art,for example as depicted in Scheme 2a.

This is accomplished in two steps from a di-C₁₋₆-alkylmalonate, oneparticularly useful di-C₁₋₆-alkylmalonate is diethyl malonate 5.Cyclization to the C5-Z-substituted-4,6-dihydroxypyrimidine 8 isachieved via an initial alkali metal base catalysed deprotonation,alkylation strategy or via generation of the monoanion using sodium/EtOHfollowed by alkylation using Z-Hal, subsequent reaction of monoalkylspecies 6 with formamidine in the presence of an alkali metal alkoxide,by mixing the malonate and all or part of the formamidine with thealkoxide or with the alkoxide and the rest of the formamide. Alternativereagents such as dimethylmalonate, sodium methoxide, formamide, in lowmolecular weight alcoholic solvents, including methanol, ethanol,2-propanol and the like, may be utilized in the synthesis by heating ata temperature range between about 80° C. to about 100° C. for about 30mins to about 90 mins followed by a mineral acid work up. In a preferredvariation chlorinated intermediate 6.1 may be used as a starting pointto obtain pyrimidines wherein alternate C5 substituents such asR_(g)R_(h)N are introduced by performing thermal nucleophilicdisplacements. Preparation of dihydroxypyrimidines can also be achievedusing microorganisms such as Rhodococcus (see for reference WO97008152A1). An ortho metallation strategy can be utilized to facilitateC3-alkylation of the corresponding 2,4-dichloropyridyl core 15. Usingn-BuLi at −78° C. under anhydrous/inert conditions followed by trappingof the resulting monoanion with an appropriate alkyl bromide or iodide(Scheme 2c) [for references see Mongin, F.; Queguiner, G. Advances inthe directed metallation of azines and diazines (pyridines, pyrimidines,pyrazines, pyridazines, quinolines, benzodiazines and carbolines). Part1: Metallation of pyridines, quinolines and carbolines. Tetrahedron(2001), 57(19), 4059-4090. Turck, A.; Ple, N.; Mongin, F.; Queguiner, G.Advances in the directed metalation of azines and diazines (pyridines,pyrimidines, pyrazines, pyridazines, quinolines, benzodiazines andcarbolines). Part 2. Metalation of pyrimidines, pyrazines, pyridazinesand benzodiazines. Tetrahedron (2001), 57(21), 4489-4505]

Chlorination of the 4 and 6 ring positions to produce intermediate 8maybe carried out by reacting 8 with a chlorinating reagent, such as,phosgene, POCl₃ (for reference see A. Gomtsyan et al., J. Med. Chem.2002, 45, 3639-3648), thionyl chloride, oxalyl chloride and by mixturesof the above reagents including PCl₃/POCl₃ at elevated reactiontemperatures.

In some embodiments of the current invention alternate functionalitiesare required at the C5 pyrimidinyl position to achieve the desiredbiological outcome. Such functionality may be introduced via a broadrange of organic synthetic procedures. Some examples are depicted inScheme 2b, wherein common intermediate 10 can be converted tointermediates such as 11, 12, 13 by synthetic chemistries familiar tothose in the art. Schemes 2bii and 2biii are initially reliant upon theone pot chlorinating formylation variant of the Villsmeier-Haackreaction which introduces “synthetic handles” at ring positions 3, 4 and5 of the core simultaneously (for references see; Chlorinatingformylation reactions with pyrimidines. Kloetzer, W.; Herberz, M.,Monatshefte fuer Chemie (1965), 96(5), 1567-72. Also see Gontsyan et alJournal of Medicinal Chemistry, 2002, 45, 3639-3648 and referencestherein). Wherein Z=nitro, commercially available2,6-dichlor-5-nitropyrimidine was utilized. Where necessary all dichlorointermediate pyrimidines (9.1, 11, 12, 13 etc) that are used as corebuilding blocks in the present invention may be optionally converted to4,6-diiodopyrimidines by halo exchange using sodium iodide and 45%hydroiodic acid as depicted in Scheme 2a.

Conventional thermal aromatic substitution reactions of amines andalcohols with halogenated pyrimidines have been well documented (see forexample A. G. Arvanitis et al., J. Medicinal Chemistry, 1999, 42,805-818 and references therein). Nucleophilic aromatic (SN_(Ar))substitution reactions of electron deficient halogenated pyrimidines areusually rapid and high yielding. However, in certain cases, such aselectron rich or neutral halogenated heterocycles, successfulsubstitution is afforded by prolonged heating.

To facilitate rapid entry into many of the compounds of the inventionmicrowave synthesis was utilized (Schemes 3 and 4). The Smithsynthesizer from Personal Chemistry is a commercially available focusedfield heating instrument that provides safer and more uniform conditionsfor performing the base catalyzed substitution reactions depicted inSchemes 3a, 3b and 3c. Bases employed for such conversions (whereby Q=N)include tertiary amines such as triethylamine, Hunig's base (i.e.diisopropyl-ethylamine), N-methylmorpholine and the like. Alternatively,one skilled in the art can employ alkali metal hydrides, alkali metalcarbonates (such as, Li₂CO₃, Na₂CO₃, K₂CO₃ and the like), an alkalimetal hydrogencarbonate (such as, LiHCO₃, NaHCO₃, KHCO₃ and the like).Wherein Q=N, inert lower alkyl alcoholic solvent can be emplyed (suchas, MeOH, EtOH, i-PrOH, n-BuOH and the like) or wherein Q=O, an etherealsolvent such as tetrahydrofuran, 1,4-dioxane, and the like can be used.Reaction times to access typical monosubstituted intermediates such as,15 and 16, can range from about 300 s to about 3000 s and whenconventional thermal methods are employed (wherein Q=0) about 20 mins toabout 120 mins.

Methods for conversion of intermediate monosubstituted pyrimidines andpyridines 15 and 16 are illustrated in Scheme 4. Examples wherein Q=NR₆(Schemes 4a, 4b and 4d) were obtained using palladium catalysedaminations. This synthetic strategy has emerged as a powerful tool forsynthesis of substituted aryl and heteroaryl anilines in recent times(for reference see S. L. Buchwald., Top. Curr. Chem., 2002, 219, 131 andreferences therein). Reaction of a suitably substituted amine (such as,intermediate 17) in the presence of a palladium or alternativetransition metal catalyst selected from but not limited to Pd₂(dba)₃,Pd(OAc)₂, CuI, Cu(OTf)₂, Ni(COD)₂, Ni(acac)₂ in a suitable anhydroussolvent (such as, THF, 1,4-dioxane, and the like) with as strong alkalimetal alkoxide base (such as, NaO^(t)Bu, KO^(t)Bu and the like). Asuitable ligand employed in this step can be selected from BINAP,P(o-tolyl)₃, tBu₃P, DPPF, P[N(^(t)Bu)CH₂CH₃]₃N and the like when thecatalyst is a palladium derived complex.

Alternatively, for “Ullman-type” aryl aminations catalysed by copperderived complexes the base employed maybe selected from an alkali metalcarbonate in an aprotic polar solvent (such as N,N-dimethylacetamide,DMF, DMSO, and the like) with L-proline, N-methylglycine ordiethylsalicyclamide as the ligand (for reference see D. Ma, OrganicLett., 2003, 5, 14, 2453-2455).

Compounds of general formula 19 to 22 may also be obtained by reversingthe order of the reaction steps (i.e. introduction of W followed by Q),wherein the initial step comprises of introduction of eitherIntermediate 17 or 18 by using base in ^(i)PrOH followed by addition of4N HCl in dioxane.

As illustrated in Scheme 5, a similar transition metal catalysedcouplings were utilized to obtain molecules of general formula 24 and 27(Scheme 5.1) wherein the Ar₁ substituent (Hal=Br, I) of intermediate 23is modified to give analogs with alkyl amino substituents (i.e.,NR_(a)R_(b), wherein R. and R_(b) are each independently H, C₁₋₆ alkylor a substituted C₁₋₆ alkyl, or R_(a) and R_(b) together with thenitrogen form a heterocyclic ring, as described herein). Alternatively,the linker atom can be oxygen by utilizing the CuI catalysed method foraromatic C—O formation described by Buchwald (see for reference S. L.Buchwald; Organic Lett., 2002, 4, 6, 973-976) by utilizing, for example,10 mol % CuI, 20 mol % 1,10-phenanthroline, 2 equivalents of Cs₂CO₃, at110° C. for 18 h (Scheme 5d), with an Ar₁ iodo substitution in thesubstrate. Additional important organometallic transformations from halointermediates 23 to active analogues of the current invention includethe well know palladium catalyzed couplings of appropriately substitutedaryl boronic acids via the “Suzuki coupling reaction” (Scheme 5e).

The Suzuki coupling represents a widely used method for the synthesis ofbiaryl compounds and is already applied on industrial scale. For a longtime this reaction was limited to the use of aryl bromides, aryl iodidesor electron-deficient aryl chlorides as starting materials. Thus, ageneral approach to the desired biaryl compounds using the cheap andeasy available aryl chlorides was not available. In the last two years,however, several new protocols for the Suzuki coupling with arylchlorides were developed. These methods allow an efficient synthesis ofbiaryls, independently of the substitution pattern and electronicproperties of the starting materials. These concepts which weredeveloped by the research groups of Fu, Buchwald, Guram, Beller as wellas Trudell and Nolan are highlighted in “Modern methods of the Suzukicross coupling: the long expected general synthetic routes using arylchlorides. Groger, Harald, Journal fuer Praktische Chemie (Weinheim,Germany) (2000), 342(4), 334-339. Alternatively additional functionalitymaybe introduced using other metal catalyzed transformations such ascyanation using zinc(II) cyanide under microwave irradiation conditionsto obtain compounds of general formula 25 or the well documented Pdcatalyzed “Sonogashira reaction” (Scheme 5c) for introduction ofterminal alkynes. Most recently the Sonogashira Coupling has beendescribed to produce almost quantitative yields of desired product usingappropriate reaction conditions in the complete absence of palladiumcatalysts (for ref see “First Examples of Transition-Metal FreeSonogashira-Type Couplings” Leadbeater, Nicholas E.; Marco, Maria;Tominack, Bonnie J, Organic Letters (2003), 5(21), 3919-3922, and alsoalso Transition-metal-free Sonogashira-type coupling reactions in water,Appukkuttan, Prasad; Dehaen, Wim; Van der Eycken, Erik, European Journalof Organic Chemistry (2003), (24), 4713-4716. In other preferredembodiments of the present invention, such organotransition metalchemistries may be used to introduce similar functional groups to the C5position or the C3 position of the respective pyrimidine and pyridylcores. For example C5 bromo or iodo intermediates may be cyanated oralkynylated as depicted in Schemes 5.2 and 5.3. Indeed, advanced nitrilederivatives of the present invention may be optionally modified viasynthetic manipulations outlined in Schemes 5.1f and Schemes 5.2a-c.

One particular embodiment is when the Hal group on Ar is located at thepara position of a phenyl ring (Ar). In another particular emdodiment ofthe invention, the Hal group is chloro at the 2 position of atrisubstituted pyridyl moiety (intermediate 28). Organotransition metalcatalysed methods for substitution of this halogen are depicted inScheme 6.

A particular substitution for compounds 19-29 is wherein D=NCOOR_(c)wherein R_(c) is C₁₋₆ alkyl, or C₃₋₇ cycloalkyl and each can be furthersubstituted. Urethanes of this type can be prepared directly fromintermediates depicted in Schemes 3 and 4 when D=NH. In certainreactions, use of a suitable nitrogen protecting group (such as,^(t)Boc, Cbz, Moz, Alloc, Fmoc and the like) may be necessary duringfurther chemical modification of the core. Deprotection maybe achievedusing standard reagents familiar to one skilled in the art (these mightinclude TFA, mineral acid, Palladium/hydrogen gas and the like in analcoholic or ethereal solvent system chosen from methanol, ethanol,tert-butanol, THF, 1,4-dioxane, and the like). On occasion wherein thetarget molecule contains 2 protecting groups, an orthogonal protectionstrategy may be adopted. The deprotected secondary amine (D=NH) cansubsequently be modified accordingly.

Schemes 7 and 8 and 9 illustrate such chemistries wherein generation ofa carbamate, urea or amide can be executed using an appropriate reactionin the presence of a base, for example, a tertiary amine base such asTEA, DIEA and the like, in an inert solvent system.

As illustrated in Scheme 7, urethane 19 can be obtained by a urethanereaction using R_(c)OCO-halide (wherein R_(a) is as described supra, andhalide is chloro, bromo, or iodo, particularly useful is chloro) in aninert solvent with or without a base. Suitable bases include an alkalimetal carbonate (such as, sodium carbonate, potassium carbonate, and thelike), an alkali metal hydrogencarbonate (such as, sodiumhydrogencarbonate, potassium hydrogencarbonate, and the like), an alkalihydroxide (such as, sodium hydroxide, potassium hydroxide, and thelike), a tertiary amine (such as, N,N-diisopropylethylamine,triethylamine, N-methylmorpholine, and the like), or an aromatic amine(such as, pyridine, imidazole, poly-(4-vinylpyridine), and the like).The inert solvent includes lower halocarbon solvents (such as,dichloromethane, dichloroethane, chloroform, and the like), etherealsolvents (such as, tetrahydrofuran, dioxane, and the like), aromaticsolvents (such as, benzene, toluene, and the like), or polar solvents(such as, N,N-dimethylformamide, dimethyl sulfoxide, and the like).Reaction temperature ranges from about −20° C. to 120° C., preferablyabout 0° C. to 100° C.

As shown in Scheme 8a, the amine intermediate obtained from acidicdeprotection of 30 can be functionalized to amides represented byspecies 32. Carbamate 20 is first reacted with 4N HCl in dioxane oralternatively TFA in dichloromethane and further reacted with acarboxylic acid (R_(d)CO₂H, wherein as used in Scheme 8a, R_(d) is Ar,or a C₁₋₆-alkylene-Ar; Ar can be substituted or unsubstituted and hasthe same meaning as described herein) with a dehydrating condensingagent in an inert solvent with or without a base to provide the amide 23of the present invention. The dehydrating condensing agent includesdicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl),bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP),benzotriazoloyloxytris(dimethylamino)-phosphonium hexafluorophosphate(BOP), O-(7-azabenzo triazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), or1-cyclohexyl-3-methylpolystyrene-carbodiimide. The base includes atertiary amine (such as, N,N-diisopropylethylamine, triethylamine, andthe like). The inert solvent includes lower halocarbon solvents (suchas, dichloromethane, dichloroethane, chloroform, and the like), etherealsolvents (such as, tetrahydrofuran, dioxane, and the like), nitrilesolvents (such as, acetonitrile, and the like), amide solvents(N,N-dimethylformamide, N,N-dimethylacetamide, and the like) andmixtures thereof. Optionally, 1-hydroxybenzotriazole (HOBT),HOBT-6-carboxaamidomethyl polystyrene, or 1-hydroxy-7-azabenzotriazole(HOAT) can be used as a reactant agent. Reaction temperature ranges fromabout −20° C. to 50° C., preferably about 0° C. to 40° C.

Alternatively, amides 32 of the present invention can be obtained by anamidation reaction using an acid halide (such as, R_(d)COCl) and a basein an inert solvent (Scheme 8a). The base includes an alkali metalcarbonate (such as, sodium carbonate, potassium carbonate, and thelike), an alkali metal hydrogencarbonate (such as, sodiumhydrogencarbonate, potassium hydrogencarbonate, and the like), an alkalihydroxide (such as, sodium hydroxide or potassium hydroxide, and like),a tertiary amine (such as, N,N-diisopropylethylamine, triethylamine,N-methylmorpholine, and the like), or an aromatic amine (such as,pyridine, imidazole, poly-(4-vinylpyridine), and the like). The inertsolvent includes lower halocarbon solvents (such as, dichloromethane,dichloroethane, chloroform, and the like), ethereal solvents (such as,tetrahydrofuran, dioxane, and the like), amide solvents (such as,N,N-dimethylacetamide, N,N-dimethylformamide, and the like), aromaticsolvents (benzene, toluene, pyridine, and the like) and mixturesthereof. Reaction temperature ranges from about −20° C. to 50° C.,preferably about 0° C. to 40° C.

Also illustrated in Scheme 8, amide 32 can be reacted with a reducingagent in an inert solvent to provide the amine 33 of the presentinvention. The reducing agent includes alkali metal aluminum hydrides(such as, lithium aluminum hydride, and the like), alkali metalborohydrides (such as, lithium borohydride, and the like), alkali metaltrialkoxyaluminum hydrides (such as, lithium tri-tert-butoxyaluminumhydride, and the like), dialkylaluminum hydrides (such as,di-isobutylaluminum hydride, and the like), borane, dialkylboranes (suchas, di-isoamyl borane, and the like), alkali metal trialkylboronhydrides (such as, lithium triethylboron hydride, and the like). Theinert solvent includes ethereal solvents (such as, tetrahydrofuran,dioxane, and the like), aromatic solvents (such as, toluene, and thelike) and mixtures thereof. Reaction temperature ranges from about −78°C. to 200° C., such as, about 50° C. to 120° C.

Alternatively, the amine 33 of the present invention can be obtained bya reductive amination reaction using the acid deprotected secondaryamine intermediate with an aldehyde (R₆CHO) and a reducing agent in aninert solvent with or without an acid. The reducing agent includessodium triacetoxyborohydride, sodium cyanoborohydride, sodiumborohydride, borane-pyridine complex, and the like. The inert solventincludes lower alkyl alcohol solvents (such as, methanol, ethanol, andthe like), lower halocarbon solvents (such as, dichloromethane,dichloroethane, chloroform, and the like), ethereal solvents (such as,tetrahydrofuran, dioxane, and the like), aromatic solvents (such as,benzene, toluene, and the like) and mixtures thereof. The acid includesan inorganic acid (such as, hydrochloric acid, sulfuric acid, and thelike) or an organic acid (such as, acetic acid, and the like). Reactiontemperature ranges from about −20° C. to 120° C., preferably about 0° C.to 100° C. In addition, this reaction can optionally be carried outunder microwave conditions. In an alternative manner, the intermediateamine product of acid deprotection of 30 can be alkylated directly withan alkylating agent, such as R₆-halide (wherein R₆ is substituted orunsubstituted C₁₋₆ alkyl, or substituted or unsubstituted C₁₋₆ alkyl-Ar,and halide is chloro, bromo and iodo), in the presence of a base and inan inert solvent to provide amine 33. The base includes an alkali metalcarbonate (such as, sodium carbonate, potassium carbonate, and thelike), an alkali metal hydride (such as, sodium hydride, potassiumhydride, and the like), alkali metal alkoxide (such as, potassiumtert-butoxide, sodium tert-butoxide, and the like); alkyl lithiums (suchas, tert-butyl lithium, n-butyl lithium and the like). The inertsolvents include, ethereal solvents (such as, tetrahydrofuran, dioxane),aromatic solvents (such as, benzene, toluene, and the like), amidesolvents (such as, N,N-dimethylformamide, and the like) and mixturesthereof. Reaction temperature ranges from about −20° C. to 120° C.,preferably about 0° C. to 100° C.

Also shown in Scheme 8 is the preparation of additional compounds of theinvention via alkylating the nitrogen of ureas represented by 32 with analkyl-halide (wherein halide is chloro, bromo and iodo) in the presenceof a base in an inert solvent to provide di-substituted urea. The baseincludes an alkali metal hydride (such as, sodium hydride, potassiumhydride, and the like), alkali metal alkoxide (such as, potassiumtert-butoxide, sodium tert-butoxide, and the like); alkyl lithiums (suchas, tent-butyl lithium, n-butyl lithium and the like). The inertsolvents include, ethereal solvents (such as, tetrahydrofuran, dioxane),aromatic solvents (such as, benzene, toluene, and the like), amidesolvents (such as, N,N-dimethylformamide, and the like) and mixturesthereof. Reaction temperature ranges from about −20° C. to 120° C.,preferably about 0° C. to 100° C.

In addition, as illustrated in Scheme 9a, urea 34 can be obtained fromdeprotecting common intermediate 30 and allowing the amine (i.e., D=NH)to react with a variety isocyanates (R_(a) NCO, wherein R_(a) has thesame meaning as described herein) in an inert solvent with or without abase. Suitable bases include an alkali metal carbonate (such as, sodiumcarbonate, potassium carbonate, and the like), an alkali metalhydrogencarbonate (such as, sodium hydrogencarbonate, potassiumhydrogencarbonate, and the like), an alkali hydroxide (such as, sodiumhydroxide, potassium hydroxide, and the like), a tertiary amine (suchas, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, andthe like), or an aromatic amine (such as, pyridine, imidazole, and thelike). The inert solvent includes lower halocarbon solvents (such as,dichloromethane, dichloroethane, chloroform, and the like), etherealsolvents (such as, tetrahydrofuran, dioxane, and the like), aromaticsolvents (such as, benzene, toluene, and the like), or polar solvents(such as, N,N-dimethylformamide, dimethyl sulfoxide, and the like).Reaction temperature ranges from about −20° C. to 120° C., preferablyabout 0° C. to 100° C.

Further, as illustrated in Scheme 9 b, thiourea 35 can be obtained fromdeprotecting common intermediate 30 and allowing the amine (i.e., D=NH)to react with a variety thioisocyanates (R_(a)NCS, wherein R_(a) has thesame meaning as described herein) in an inert solvent with or without abase. Suitable bases include an alkali metal carbonate (such as, sodiumcarbonate, potassium carbonate, and the like), an alkali metalhydrogencarbonate (such as, sodium hydrogencarbonate, potassiumhydrogencarbonate, and the like), an alkali hydroxide (such as, sodiumhydroxide, potassium hydroxide, and the like), a tertiary amine (suchas, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, andthe like), or an aromatic amine (such as, pyridine, imidazole, and thelike). The inert solvent includes lower halocarbon solvents (such as,dichloromethane, dichloroethane, chloroform, and the like), etherealsolvents (such as, tetrahydrofuran, dioxane, and the like), aromaticsolvents (such as, benzene, toluene, and the like), or polar solvents(such as, N,N-dimethylformamide, dimethyl sulfoxide, and the like).Reaction temperature ranges from about −20° C. to 120° C., preferablyabout 0° C. to 100° C.

Scheme 10 illustrates the synthesis of para-alkyl sulfones (37) whichare used as aryl building blocks in Scheme 4 of the present invention,wherein R₁₀-R₁₃ have the same meaning as described herein. The commonmethods for preparing these sulfones include the oxidation of sulfidesor the sulfonylation of arenes using aryl sulfonyl halides or arylsulfonic acids in the presence of a strong acid catalyst (see forgeneral reference: the Organic Chemistry of Sulfur; Oae S., Ed.; PlenumPress: New York, 1977). Optimal conversion to the optionally2,5-disubstituted arene 37 was achieved thermally wherein Hal ispreferably iodo using 5 mol % (CuOTO₂.PhH and 10 mol %N,N′-dimethylethylenediamine in DMSO by the method of Wang et al (seefor reference Wang Z.; Baskin J. M., Org. Lett., 2002, 4, 25,4423-4425). In some embodiments, R₁₀ and R₁₃ are each independently H,halogen, or C₁₋₆ alkyl; R₁₁ and R₁₂ are both H; Hal=Br, I; and Q1=OH, orNH₂.

Alternative standard organic synthetic methods may be used to introducealternate substituents in to the Ar component. In one example whereinthe linker atom is Q=N, the manipulation maybe carried out by protectingthe aniline amino functionality using standard FmocCl and CbzClprotection deprotection steps familiar to one skilled in the art (Scheme11, wherein R₁₀-R₁₃ have the same meaning as described herein) andsubsequently using the deprotected aniline in subsequent steps such asthose depicted in Scheme 4. Nitrile 39, maybe alternatively transformedin to amidines (see Table of compounds) by using hydroxylamine HClfollowed by reduction using zinc/acetic acid. In some embodiments of theinvention R₁₀ is halogen, and R₁₃ is H or halogen.

Synthetic scheme 11.1, depicts some of organic synthetic strategies ofthe current invention for accessing advanced aromatic building blocksrequired for use in scheme 4c wherein R₁₀-R₁₃ are preferably halogen,alkoxy or short alkyl. Following incorporation in to analogues of thepresent invention via methodologies depicted in scheme 4c, intermediatessuch as those of type 38.3 may be deprotected through use of suitablesilyl deprotection agents such as TBAF or HF. Resulting terminalalcohols may be optionally further modified (for ref see T. Matsui etal., Biorg. Med. Chem., 10, 2002, 3787).

Synthesis of the 3,5-oxadiazolo variant is depicted in Scheme 12.Zinc(II) chloride catalyzed coupling of amidoxime 44 with4-hydroxypiperidine, CNBr derived 46 yielded building block 47 afteracidic workup, which was subsequently utilized in reaction sequencesdepicted as illustrated in Scheme 3.

In a preferred embodiment of the present invention a sulfonamide groupmay be introduced into the meta or para Ar position. This can beaccomplished via several amenable synthetic multi step manipulationsincluding the reaction of ammonia with sulfonyl chlorides (Scheme 13A)or alternatively sulfonamides can be obtained by reacting sulfinic acidsalts with an electrophilic nitrogen source such ashydroxylamine-O-sulfonic acid orbis-(2,2,2-trichloroethyl)-azodicarboxylate. Preferably3-methoxy-3-oxapropane-1-sulfinate can serve as a sulfinate donor moietythrough a simple alkylation and be subsequently removed via abeta-elimination reaction. Reaction of the resulting sulfinate with anelectrophilic nitrogen source provides the primary sulfonamide analogueof the current invention. Such intermediates may be optionally furthermodified to amides such as those represented by general formula 49.Acylsulfonamides of this type can be obtained by an amidation reactionusing an acid halide or anhydride (such as, R_(g)COCl or (R_(g)CO)₂O)and a base in an inert solvent (Scheme 13C). The base includes an alkalimetal carbonate (such as, sodium carbonate, potassium carbonate, and thelike), an alkali metal hydrogencarbonate (such as, sodiumhydrogencarbonate, potassium hydrogencarbonate, and the like), an alkalihydroxide (such as, sodium hydroxide or potassium hydroxide, and like),a tertiary amine (such as, N,N-diisopropylethylamine, triethylamine,N-methylmorpholine, and the like), or an aromatic amine (such as,pyridine, imidazole, poly-(4-vinylpyridine), and the like). The inertsolvent includes lower halocarbon solvents (such as, dichloromethane,dichloroethane, chloroform, and the like), ethereal solvents (such as,tetrahydrofuran, dioxane, and the like), amide solvents (such as,N,N-dimethylacetamide, N,N-dimethylformamide, and the like), aromaticsolvents (benzene, toluene, pyridine, and the like) and mixturesthereof. Reaction temperature ranges from about −20° C. to 50° C.,preferably about 0° C. to 40° C.

The compounds of the present invention may be prepared according to thegeneral synthetic schemes as described herein as well as relevantpublished literature procedures that are used by one skilled in the art.Exemplary reagents and procedures for these reactions appear hereinafterin the working Examples. Protection and deprotection may be carried outby procedures generally known in the art (see, for example, Greene, T.W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3^(rd)Edition, 1999 [Wiley]; incorporated herein by reference in itsentirity).

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of Formula (I).Separation of the individual isomers or selective synthesis of theindividual isomers is accomplished by application of various methodswhich are well known to practitioners in the art.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of Formula (I).Separation of the individual isomers or selective synthesis of theindividual isomers is accomplished by application of various methodswhich are well known to practitioners in the art.

Indications and Methods of Prophylaxis and/or Treatment

In addition to the foregoing beneficial uses for compounds of thepresent invention disclosed herein, compounds of the invention areuseful in the treatment of additional diseases. Without limitation,these include the following.

The most significant pathologies in Type II diabetes are impairedinsulin signaling at its target tissues (“insulin resistance”) andfailure of the insulin-producing cells of the pancreas to secrete anappropriate degree of insulin in response to a hyperglycemic signal.Current therapies to treat the latter include inhibitors of the β-cellATP-sensitive potassium channel to trigger the release of endogenousinsulin stores, or administration of exogenous insulin. Neither of theseachieves accurate normalization of blood glucose levels and both carrythe risk of inducing hypoglycemia. For these reasons, there has beenintense interest in the development of pharmaceuticals that function ina glucose-dependent action, i.e. potentiators of glucose signaling.Physiological signaling systems which function in this manner arewell-characterized and include the gut peptides GLP1, GIP and PACAP.These hormones act via their cognate G-protein coupled receptor tostimulate the production of cAMP in pancreatic β-cells. The increasedcAMP does not appear to result in stimulation of insulin release duringthe fasting or preprandial state. However, a series of biochemicaltargets of cAMP signaling, including the ATP-sensitive potassiumchannel, voltage-sensitive potassium channels and the exocytoticmachinery, are modified in such a way that the insulin secretoryresponse to a postprandial glucose stimulus is markedly enhanced.Accordingly, agonists of novel, similarly functioning, β-cell GPCRs,including RUP3, would also stimulate the release of endogenous insulinand consequently promote normoglycemia in Type II diabetes.

It is also established that increased cAMP, for example as a result ofGLP1 stimulation, promotes β-cell proliferation, inhibits β-cell deathand thus improves islet mass. This positive effect on β-cell mass isexpected to be beneficial in both Type II diabetes, where insufficientinsulin is produced, and Type I diabetes, where β-cells are destroyed byan inappropriate autoimmune response.

Some β-cell GPCRs, including RUP3, are also present in the hypothalamuswhere they modulate hunger, satiety, decrease food intake, controllingor decreasing weight and energy expenditure. Hence, given their functionwithin the hypothalamic circuitry, agonists or inverse agonists of thesereceptors mitigate hunger, promote satiety and therefore modulateweight.

It is also well-established that metabolic diseases exert a negativeinfluence on other physiological systems. Thus, there is often thecodevelopment of multiple disease states (e.g. type I diabetes, type IIdiabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, obesity or cardiovascular disease in“Syndrome X”) or secondary diseases which clearly occur secondary todiabetes (e.g. kidney disease, peripheral neuropathy). Thus, it isexpected that effective treatment of the diabetic condition will in turnbe of benefit to such interconnected disease states.

In some embodiments of the present invention the metabolic-relateddisorder is hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus,idiopathic type 1 diabetes (Type Ib), latent autoimmune diabetes inadults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypicaldiabetes (YOAD), maturity onset diabetes of the young (MODY),malnutrition-related diabetes, gestational diabetes, coronary heartdisease, ischemic stroke, restenosis after angioplasty, peripheralvascular disease, intermittent claudication, myocardial infarction (e.g.necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditionsof impaired glucose tolerance (IGT), conditions of impaired fastingplasma glucose, metabolic acidosis, ketosis, arthritis, obesity,osteoporosis, hypertension, congestive heart failure, left ventricularhypertrophy, peripheral arterial disease, diabetic retinopathy, maculardegeneration, cataract, diabetic nephropathy, glomerulosclerosis,chronic renal failure, diabetic neuropathy, metabolic syndrome, syndromeX, premenstrual syndrome, coronary heart disease, angina pectoris,thrombosis, atherosclerosis, myocardial infarction, transient ischemicattacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia,hyperlipidemia, hypertrygliceridemia, insulin resistance, impairedglucose metabolism, conditions of impaired glucose tolerance, conditionsof impaired fasting plasma glucose, obesity, erectile dysfunction, skinand connective tissue disorders, foot ulcerations and ulcerativecolitis, endothelial dysfunction and impaired vascular compliance.

One aspect of the present invention pertains to methods for treatment ofa metabolic-related disorder in an individual comprising administeringto the individual in need of such treatment a therapeutically effectiveamount of a compound as described herein or a pharmaceutical compositionthereof. In some embodiments the metabolic-related disorder is type Idiabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. In some embodimentsthe metabolic-related disorder is type II diabetes. In some embodimentsthe metabolic-related disorder is hyperglycemia. In some embodiments themetabolic-related disorder is hyperlipidemia. In some embodiments themetabolic-related disorder is hypertriglyceridemia. In some embodimentsthe metabolic-related disorder is type I diabetes. In some embodimentsthe metabolic-related disorder is dyslipidemia. In some embodiments themetabolic-related disorder is syndrome X. In some embodiments theindividual is a mammal. In some embodiments the mammal is a human.

One aspect of the present invention pertains to methods of decreasingfood intake of an individual comprising administering to the individualin need thereof a therapeutically effective amount of a compound of thepresent invention or pharmaceutical composition thereof. In someembodiments the individual is a mammal. In some embodiments the mammalis a human.

One aspect of the present invention pertains to methods of inducingsatiety in an individual comprising administering to the individual inneed of such treatment a therapeutically effective amount of a compoundof the present invention or pharmaceutical composition thereof. In someembodiments the individual is a mammal. In some embodiments the mammalis a human.

One aspect of the present invention pertains to methods of controllingor decreasing weight gain of an individual comprising administering tothe individual in need of such treatment a therapeutically effectiveamount of a compound of the present invention or pharmaceuticalcomposition thereof. In some embodiments the individual is a mammal. Insome embodiments the mammal is a human.

Some embodiments of the present invention pertain to methods wherein thehuman has a body mass index of about 18.5 to about 45. In someembodiments, the human has a body mass index of about 25 to about 45. Insome embodiments, the human has a body mass index of about 30 to about45. In some embodiments, the human has a body mass index of about 35 toabout 45.

One aspect of the present invention pertains to methods of modulating aRUP3 receptor in an individual comprising contacting the receptor with acompound of the present invention or pharmaceutical composition thereof.In some embodiments, the compound is an agonist. In some embodiments,the compound is an inverse agonist. In some embodiments, the compound isan antagonist. In some embodiments, the modulation of the RUP3 receptoris treatment of a metabolic-related disorder and complications thereof.In some embodiments, the metabolic-related disorder is type I diabetes,type II diabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. In some embodiments,the metabolic-related disorder is type II diabetes. In some embodiments,the metabolic-related disorder is hyperglycemia. In some embodiments,the metabolic-related disorder is hyperlipidemia. In some embodiments,the metabolic-related disorder is hypertriglyceridemia. In someembodiments, the metabolic-related disorder is type I diabetes. In someembodiments, the metabolic-related disorder is dyslipidemia. In someembodiments, the metabolic-related disorder is syndrome X. In someembodiments, the individual is a mammal. In some embodiments, the mammalis a human.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor reduces food intake of the individual. In some embodiments theindividual is a mammal. In some embodiments the mammal is a human. Insome embodiments the human has a body mass index of about 18.5 to about45. In some embodiments the human has a body mass index of about 25 toabout 45. In some embodiments the human has a body mass index of about30 to about 45. In some embodiments the human has a body mass index ofabout 35 to about 45.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor induces satiety in the individual. In some embodiments theindividual is a mammal. In some embodiments the mammal is a human. Insome embodiments the human has a body mass index of about 18.5 to about45. In some embodiments the human has a body mass index of about 25 toabout 45. In some embodiments the human has a body mass index of about30 to about 45. In some embodiments the human has a body mass index ofabout 35 to about 45.

Some embodiments of the present invention include a method of modulatinga RUP3 receptor in an individual comprising contacting the receptor witha compound of the present invention wherein the modulation of the RUP3receptor controls or reduces weight gain of the individual. In someembodiments the individual is a mammal. In some embodiments the mammalis a human. In some embodiments the human has a body mass index of about18.5 to about 45. In some embodiments the human has a body mass index ofabout 25 to about 45. In some embodiments the human has a body massindex of about 30 to about 45. In some embodiments the human has a bodymass index of about 35 to about 45.

One aspect of the present invention pertains to use of a compound asdescribed herein, for production of a medicament for use in treatment ofa metabolic-related disorder. In some embodiments, the metabolic-relateddisorder is type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X.

One aspect of the present invention pertains to use of a compound asdescribed herein, for production of a medicament for use in decreasingfood intake of an individual. In some embodiments, the individual is amammal. In some embodiments, the mammal is a human. In some embodiments,the human has a body mass index of about 18.5 to about 45. In someembodiments, the human has a body mass index of about 25 to about 45. Insome embodiments, the human has a body mass index of about 30 to about45. In some embodiments, the human has a body mass index of about 35 toabout 45.

One aspect of the present invention pertains to use of a compound asdescribed herein, for production of a medicament for use of inducingsatiety in an individual. In some embodiments, the individual is amammal. In some embodiments, the mammal is a human. In some embodiments,the human has a body mass index of about 18.5 to about 45. In someembodiments, the human has a body mass index of about 25 to about 45. Insome embodiments, the human has a body mass index of about 30 to about45. In some embodiments, the human has a body mass index of about 35 toabout 45.

One aspect of the present invention pertains to use of a compound asdescribed herein, for production of a medicament for use in controllingor decreasing weight gain in an individual. In some embodiments, theindividual is a mammal. In some embodiments, the mammal is a human. Insome embodiments, the human has a body mass index of about 18.5 to about45. In some embodiments, the human has a body mass index of about 25 toabout 45. In some embodiments, the human has a body mass index of about30 to about 45. In some embodiments, the human has a body mass index ofabout 35 to about 45.

One aspect of the present invention pertains to a compound, as describedherein, for use in a method of treatment of the human or animal body bytherapy.

One aspect of the present invention pertains to a compound, as describedherein, for use in a method of treatment of a metabolic-related disorderof the human or animal body by therapy.

One aspect of the present invention pertains to a compound, as describedherein, for use in a method of decreasing food intake of the human oranimal body by therapy.

One aspect of the present invention pertains to a compound, as describedherein, for use in a method of inducing satiety of the human or animalbody by therapy.

One aspect of the present invention pertains to a compound, as describedherein, for use in a method of controlling or decreasing weight gain ofthe human or animal body by therapy.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds of Formula (I) or anyformula disclosed herein, and one or more pharmaceutically acceptablecarriers. Some embodiments of the present invention pertain topharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier. Formulations may be prepared by anysuitable method, typically by uniformly mixing the active compound(s)with liquids or finely divided solid carriers, or both, in the requiredproportions, and then, if necessary, forming the resulting mixture intoa desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20th Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro, A. R., et al.).

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may, in an alternative use, be administered asa raw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as RUP3 receptor modulators.By the term “active ingredient” is defined in the context of a“pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits, and as is customary and is known to the physician,it is to be tailored to the individual conditions in each individualcase. It depends, for example, on the nature and severity of the illnessto be treated, on the condition of the patient, on the compound employedor on whether an acute or chronic disease state is treated orprophylaxis is conducted or on whether further active compounds areadministered in addition to the compounds of the present invention.Representative doses of the present invention include, but not limitedto, about 0.001 mg to about 5000 mg, about 0.001 to about 2500 mg, about0.001 to about 1000 mg, 0.001 to about 500 mg, 0.001 mg to about 250 mg,about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001mg to about 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3 or 4, doses. Depending on the individual and as deemedappropriate from the patient's physician or care-giver it may benecessary to deviate upward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. Typically, animal modelsinclude, but are not limited to, the rodents diabetes models asdescribed in Example 5, infra (as well as other animal models known inthe art, such as those reported by Reed and Scribner in Diabetes,Obesity and Metabolism, 1, 1999, 75-86). In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the Formula (I) and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavouringagents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavours, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of theFormula (I) or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the Formula (I) as an aerosol can be prepared by processeswell-known to the person skilled in the art. For their preparation, forexample, solutions or dispersions of the compounds of the Formula (I) inwater, water/alcohol mixtures or suitable saline solutions can beemployed using customary additives, for example benzyl alcohol or othersuitable preservatives, absorption enhancers for increasing thebioavailability, solubilizers, dispersants and others, and, ifappropriate, customary propellants, for example include carbon dioxide,CFC's, such as, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2 (1977); incorporated herein by reference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

In some embodiments the pharmaceutical agents is selected from the groupconsisting of: apolipoprotein-B secretion/microsomal triglyceridetransfer protein (apo-B/MTP) inhibitors, MCR-4 agonists,cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrinereuptake inhibitors (for example, sibutramine), sympathomimetic agensts,β₃ adrenergic receptor agonists, dopamine agonists (for example,bromocriptine), melanocyte-stimulating hormone receptor analogs,cannabinoid 1 receptor antagonists [for example, SR141716:N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide],melanin concentrating hormone antagonists, leptons (the OB protein),leptin analogues, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorecticagents (such as a bombesin agonist), Neuropeptide-Y antagonists,thyromimetic agents, dehydroepiandrosterone or an analogue thereof,glucocorticoid receptor agonists or antagonists, orexin receptorantagonists, urocortin binding protein antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neutrotrophic factors (such asAxokine™), human agouti-related proteins (AGRP), ghrelin receptorantagonists, histamine 3 receptor antagonists or reverse agonists,neuromedin U receptor agonists, noradrenergic anorectic agents (forexample, phentermine, mazindol and the like), appetite suppressants (forexample, bupropion) and the like. In further embodiments, thepharmaceutical agent is selected from the group consisting of orlistat,sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine.

In some embodiments the pharmaceutical agents is selected from the groupconsisting of: sulfonylureas, meglitinides, biguanides, α-glucosidaseinhibitors, peroxisome proliferators-activated receptor-γ (i.e., PPAR-γ)agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors,cholesterol-lowering drugs (for example, fibrates that include:fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like; bileacid sequestrants which include: cholestyramine, colestipol and thelike; and niacin), antiplatelet agents (for example, aspirin andadenosine diphosphate receptor antagonists that include: clopidogrel,ticlopidine and the like), angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists and adiponectin.

It is noted that when the RUP3 receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as RUP3receptor modulators, for the treatment of obesity in domestic animals(e.g., cats and dogs), and RUP3 receptor modulators in other domesticanimals where no disease or disorder is evident (e.g., food-orientedanimals such as cows, chickens, fish, etc.). Those of ordinary skill inthe art are readily credited with understanding the utility of suchcompounds in such settings.

Combination Therapy—Prophylaxis and Treatment

In the context of the present invention, a compound of Formula (I) orpharmaceutical composition thereof can be utilized for modulating theactivity of RUP3 receptor mediated diseases, conditions and/or disordersas described herein. Examples of modulating the activity of RUP3receptor mediated diseases include the prophylaxis or treatment ofmetabolic related disorders such as, but not limited to, type Idiabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia and syndrome X. Other examples ofmodulating the activity of RUP3 receptor mediated diseases include theprophylaxis or treatment of obesity and/or overweight by decreasing foodintake, inducing satiation (i.e., the feeling of fullness), controllingweight gain, decreasing body weight and/or affecting metabolism suchthat the recipient loses weight and/or maintains weight.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent (i.e., mono-therapy), they can also be usedin combination with other pharmaceutical agents (i.e.,combination-therapy) for the treatment of thediseases/conditions/disorders described herein. Therefore, anotheraspect of the present invention includes methods of prophylaxis and/ortreatment of a metabolic related disorder or a weight related disorder,such as obesity, comprising administering to an individual in need ofprophylaxis and/or treatment a therapeutically effective amount of acompound of the present invention, for example Formula (I), incombination with one or more additional pharmaceutical agent asdescribed herein.

Suitable pharmaceutical agents that can be used in combination with thecompounds of the present invention include anti-obesity agents such asapolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK-A)agonists, serotonin and norepinephrine reuptake inhibitors (for example,sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists,dopamine agonists (for example, bromocriptine), melanocyte-stimulatinghormone receptor analogs, cannabinoid 1 receptor antagonists [forexample, SR141716:N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide],melanin concentrating hormone antagonists, leptons (the OB protein),leptin analogues, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e., Orlistat), anorecticagents (such as a bombesin agonist), Neuropeptide-Y antagonists,thyromimetic agents, dehydroepiandrosterone or an analogue thereof,glucocorticoid receptor agonists or antagonists, orexin receptorantagonists, urocortin binding protein antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neutrotrophic factors (such asAxokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.and Procter & Gamble Company, Cincinnati, Ohio), human agouti-relatedproteins (AGRP), ghrelin receptor antagonists, histamine 3 receptorantagonists or reverse agonists, neuromedin U receptor agonists,noradrenergic anorectic agents (for example, phentermine, mazindol andthe like) and appetite suppressants (for example, bupropion).

Other anti-obesity agents, including the agents set forth infra, arewell known, or will be readily apparent in light of the instantdisclosure, to one of ordinary skill in the art.

In some embodiments, the anti-obesity agents are selected from the groupconsisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin,and pseudoephedrine. In a further embodiment, compounds of the presentinvention and combination therapies are administered in conjunction withexercise and/or a sensible diet.

It will be understood that the scope of combination-therapy of thecompounds of the present invention with other anti-obesity agents,anorectic agents, appetite suppressant and related agents is not limitedto those listed above, but includes in principle any combination withany pharmaceutical agent or pharmaceutical composition useful for thetreatment of overweight and obese individuals.

Other suitable pharmaceutical agents, in addition to anti-obesityagents, that can be used in combination with the compounds of thepresent invention include agents useful in the treatment of metabolicrelated disorders and/or concomitant diseases thereof. For example, butnot limited to, congestive heart failure, type I diabetes, type IIdiabetes, inadequate glucose tolerance, insulin resistance,hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, syndrome X, retinopathy, nephropathyand neuropathy. Prophylaxis or treatment of one or more of the diseasescited herein include the use of one or more pharmaceutical agents knownin the art belonging to the classes of drugs referred to, but notlimited to, the following: sulfonylureas, meglitinides, biguanides,α-glucosidase inhibitors, peroxisome proliferators-activated receptor-γ(i.e., PPAR-γ) agonists, insulin, insulin analogues, HMG-CoA reductaseinhibitors, cholesterol-lowering drugs (for example, fibrates thatinclude: fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like;bile acid sequestrants which include: cholestyramine, colestipol and thelike; and niacin), antiplatelet agents (for example, aspirin andadenosine diphosphate receptor antagonists that include: clopidogrel,ticlopidine and the like), angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists, adiponectin and the like. Inaccordance to one aspect of the present invention, a compound of thepresent can be used in combination with a pharmaceutical agent or agentsbelonging to one or more of the classes of drugs cited herein.

It will be understood that the scope of combination-therapy of thecompounds of the present invention with other pharmaceutical agents isnot limited to those listed herein, supra or infra, but includes inprinciple any combination with any pharmaceutical agent orpharmaceutical composition useful for the prophylaxis or treatment ofdiseases, conditions or disorders that are linked to metabolic relateddisorders.

Some embodiments of the present invention include methods of prophylaxisor treatment of a disease, disorder, condition or complication thereofas described herein, comprising administering to an individual in needof such prophylaxis or treatment a therapeutically effective amount ordose of a compound of the present invention in combination with at leastone pharmaceutical agent selected from the group consisting of:sulfonylureas, meglitinides, biguanides, α-glucosidase inhibitors,peroxisome proliferators-activated receptor-γ (i.e., PPAR-γ) agonists,insulin, insulin analogues, HMG-CoA reductase inhibitors,cholesterol-lowering drugs (for example, fibrates that include:fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like; bileacid sequestrants which include: cholestyramine, colestipol and thelike; and niacin), antiplatelet agents (for example, aspirin andadenosine diphosphate receptor antagonists that include: clopidogrel,ticlopidine and the like), angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists and adiponectin. In someembodiments, methods of the present invention include compounds of thepresent invention and the pharmaceutical agents are administeredseparately. In further embodiments, compounds of the present inventionand the pharmaceutical agents are administered together.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include sulfonylureas. Thesulfonylureas (SU) are drugs which promote secretion of insulin frompancreatic β cells by transmitting signals of insulin secretion via SUreceptors in the cell membranes. Examples of the sulfonylureas includeglyburide, glipizide, glimepiride and other sulfonylureas known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the meglitinides. Themeglitinides are benzoic acid derivatives represent a novel class ofinsulin secretagogues. These agents target postprandial hyperglycemiaand show comparable efficacy to sulfonylureas in reducing HbAl c.Examples of meglitinides include repaglinide, nateglinide and othermeglitinides known in the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the biguanides. Thebiguanides represent a class of drugs that stimulate anaerobicglycolysis, increase the sensitivity to insulin in the peripheraltissues, inhibit glucose absorption from the intestine, suppress ofhepatic gluconeogenesis, and inhibit fatty acid oxidation. Examples ofbiguanides include phenformin, metformin, buformin, and biguanides knownin the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the α-glucosidase inhibitors.The α-glucosidase inhibitors competitively inhibit digestive enzymessuch as α-amylase, maltase, a-dextrinase, sucrase, etc. in the pancreasand or small intestine. The reversible inhibition by α-glucosidaseinhibitors retard, diminish or otherwise reduce blood glucose levels bydelaying the digestion of starch and sugars. Examples of α-glucosidaseinhibitors include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine(generic name; voglibose), miglitol, and α-glucosidase inhibitors knownin the art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the peroxisomeproliferators-activated receptor-γ (i.e., PPAR-γ) agonists. Theperoxisome proliferators-activated receptor-γ agonists represent a classof compounds that activates the nuclear receptor PPAR-γ and thereforeregulate the transcription of insulin-responsive genes involved in thecontrol of glucose production, transport and utilization. Agents in theclass also facilitate the regulation of fatty acid metabolism. Examplesof PPAR-γ agonists include rosiglitazone, pioglitazone, tesaglitazar,netoglitazone, GW-409544, GW-501516 and PPAR-γ agonists known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the HMG-CoA reductaseinhibitors. The HMG-CoA reductase inhibitors are agents also referred toas Statin compounds that belong to a class of drugs that lower bloodcholesterol levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA)reductase. HMG-CoA reductase is the rate-limiting enzyme in cholesterolbiosynthesis. The statins lower serum LDL concentrations by upregulatingthe activity of LDL receptors and are responsible for clearing LDL fromthe blood. Some representative examples the statin compounds includerosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin,atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin,BMS's “superstatin”, and HMG-CoA reductase inhibitors known in the art.Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the Fibrates. Fibratecompounds belong to a class of drugs that lower blood cholesterol levelsby inhibiting synthesis and secretion of triglycerides in the liver andactivating a lipoprotein lipase. Fibrates have been known to activateperoxisome proliferators-activated receptors and induce lipoproteinlipase expression. Examples of fibrate compounds include bezafibrate,beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate,clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, theofibrate, and fibrates known inthe art.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the angiotensin convertingenzyme (ACE) inhibitors. The angiotensin converting enzyme inhibitorsbelong to the class of drugs that partially lower blood glucose levelsas well as lowering blood pressure by inhibiting angiotensin convertingenzymes. Examples of the angiotensin converting enzyme inhibitorsinclude captopril, enalapril, alacepril, delapril; ramipril, lisinopril,imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril,moveltopril, perindopril, quinapril, spirapril, temocapril,trandolapril, and angiotensin converting enzyme inhibitors known in theart.

Suitable pharmaceutical agents that can be used in conjunction withcompounds of the present invention include the angiotensin II receptorantagonists. Angiotensin II receptor antagonists target the angiotensinII receptor subtype 1 (i.e., AT1) and demonstrate a beneficial effect onhypertension. Examples of angiotensin II receptor antagonists includelosartan (and the potassium salt form), and angiotensin II receptorantagonists known in the art.

Other treatments for one or more of the diseases cited herein includethe use of pharmaceutical agents known in the art belonging to theclasses of drugs referred to, but not limited to, the following: amylinagonists (for example, pramlintide), insulin secretagogues (for example,GLP-1 agonists; exendin-4; insulinotropin (NN2211); dipeptyl peptidaseinhibitors (for example, NVP-DPP-728), acyl CoA cholesterolacetyltransferase inhibitors (for example, Ezetimibe, eflucimibe, andlike compounds), cholesterol absorption inhibitors (for example,ezetimibe, pamaqueside and like compounds), cholesterol ester transferprotein inhibitors (for example, CP-529414, JTT-705, CETi-1, and likecompounds), microsomal triglyceride transfer protein inhibitors (forexample, implitapide, and like compounds), cholesterol modulators (forexample, NO-1886, and like compounds), bile acid modulators (forexample, GT103-279 and like compounds) and squalene synthase inhibitors.

Squalene synthesis inhibitors belong to a class of drugs that lowerblood cholesterol levels by inhibiting synthesis of squalene. Examplesof the squalene synthesis inhibitors include(S)-α-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonic acid, mono potassium salt(BMS-188494) and squalene synthesis inhibitors known in the art.

In accordance with the present invention, the combination can be used bymixing the respective active components either all together orindependently with a physiologically acceptable carrier, excipient,binder, diluent, etc., as described herein above, and administering themixture or mixtures either orally or non-orally as a pharmaceuticalcomposition. When a compound or a mixture of compounds of Formula (I)are administered as a combination therapy with another active compoundthe therapeutic agents can be formulated as a separate pharmaceuticalcompositions given at the same time or at different times, or thetherapeutic agents can be given as a single composition.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of Formula (I) that would be useful not only in radio-imagingbut also in assays, both in vitro and in vivo, for localizing andquantitating the RUP3 receptor in tissue samples, including human, andfor identifying RUP3 receptor ligands by inhibition binding of aradio-labeled compound. It is a further object of this invention todevelop novel RUP3 receptor assays of which comprise such radio-labeledcompounds.

The present invention embraces isotopically-labeled compounds of Formula(I) and any subgenera herein, such as but not limited to, Formula (Ia)through Formula (Is). An “isotopically” or “radio-labeled” compounds arethose which are identical to compounds disclosed herein, but for thefact that one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ²H (also written as Dfor deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ¹²³I, ¹²⁴I, ¹²⁵Iand ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro RUP3 receptor labelingand competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I,¹³¹I, ³⁵S or will generally be most useful. For radio-imagingapplications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula (I) that has incorporated at least one radionuclide;in some embodiments the radionuclide is selected from the groupconsisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Schemes supra and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the more scarce radio-isotope ornonradio-active isotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas—This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]—This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with Lithium Aluminum Hydride [³H]—This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling—This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]—This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions—This procedure transforms an aryl orheteroaryl amine into a diazonium salt, such as a tetrafluoroboratesalt, and subsequently to ¹²⁵I labeled compound using Na¹²⁵I. Arepresented procedure was reported by Zhu, D.-G. and co-workers in J.Org. Chem. 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols—This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labeled Compd Radiopharm. 1999, 42,S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I—This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)4]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresented procedure was reported by Bas, M.-D. and co-workers in J.Labeled Compd Radiopharm. 2001, 44, S280-S282.

A radio-labeled RUP3 receptor compound of Formula (I) can be used in ascreening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula (I)” to the RUP3 receptor. Accordingly, the abilityof a test compound to compete with the “radio-labeled compound ofFormula (I)” for the binding to the RUP3 receptor directly correlates toits binding affinity.

The labeled compounds of the present invention bind to the RUP3receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 in yet another embodiment the labeled compound hasan IC₅₀ less than about 10 in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those in the art based upon, inter alia, a review of this disclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES

The examples are provided to further define the invention without,however, limiting the invention to the specifics of these examples.

Example 1 96-well Cyclic AMP Membrane Assay for RUP3 Materials:

-   1) Adenlyl cyclase Activation Flashplate Assay kit from Perkin    Elmer—96 wells (SMP004B) and ¹²⁵I tracer (NEX130) which comes with    the kit. Keep in refrigerator, in a box, and do not expose the    Flashplates to light.-   2) Phosphocreatine—Sigma P-7936-   3) Creatine Phosphokinase—Sigma C-3755-   4) GTP—Sigma G-8877-   5) ATP—Sigma A-2383-   6) IBMX—Sigma I-7018-   7) Hepes—1M solution in distilled water—Gibco #15630080-   8) MgCl2—Sigma M-1028-1M Solution-   9) NaCl—Sigma—S6546—5M Solution-   10) Bradford Protein Assay Kit—Biorad # 5000001-   11) Proclin 300—Sigma #4-8126    Binding Buffer—filter through 45-micron Nalgene filter and keep in    refrigerator. All buffers and membranes should be kept cold (in ice    bucket) while performing assay.-   20 mM Hepes, pH7.4-   1 mM MgCl2-   100 mM NaCl2-   2× Regeneration Buffer (make in binding buffer):-   20 mM Phosphocreatine (1.02 gm/200 ml binding buffer)-   20 units Creatine phosphokinase (4 mg/200 ml)-   20 uM GTP (make up 10.46 mg/ml in binding buffer and add 200 μL /200    ml)-   0.2 mM ATP (22.04 mg/200 ml)-   100 mM IBMX (44.4 mg IBMX dissolved in 1 ml 100% DMSO first and then    add the entire amount to 200 ml of buffer).    Regeneration buffer can be aliquotted into 40-45 ml portions (in 50    ml sterile tubes) and kept frozen for up to 2 months. Simply put the    tube in a beaker with room temperature water to thaw out the    regeneration buffer on the day of the assay.

A. Assay Procedure

-   -   1) Pipet 50 μL regeneration buffer in all 96 wells using Matrix        1250 8-channel pipettor.    -   2) Pipet 5 μL DMSO in columns 1 and columns 11 and 12.    -   3) Pipet 50 μL cAMP standards in columns 11 and 12 in this        format: 50 pmole/well for row A, 25 pmole/well for row B, 12.5        pmol/well for row C, 5 picomol/well for row D, 2.5 pmole/well        for row E, 1.25 pmole/well for row F, 0.5 pmole/well for row G,        and 0 pmole/well (buffer only) for row H.    -   4) Pipet 5 pd., compounds from each well of a compound dilution        plate, for IC50s, using the following dilution scheme:        -   Well H: 400 uM compound (final concentration of compound in            reaction mix=5/100×400 uM=20 uM        -   Well G: 1:10 dilution of Well H (i.e. 5 μL compound from            well H+45 μL 100% DMSO) (final concentration=2 uM)        -   Well F: 1:10 dilution of well G (final concentration=0.2 uM)        -   Well E: 1:10 dilution of well F (final concentration=0.02            uM)        -   Well D: 1:10 dilution of well E (final concentration=0.002            uM)        -   Well C: 1:10 dilution of well D (final concentration=0.0002            uM        -   Well B: 1:10 dilution of well C (final concentration=0.00002            uM)        -   Well A: 1:10 dilution of well B (final            concentration=0.000002 uM)        -   IC₅₀s or EC₅₀s are done in triplicate. One Flashplate can            therefore be set up to handle 3 compounds. (i.e., columns 2,            3, and 4 are for compound #1, columns 5, 6, and 7 are for            compound #2, and columns 8, 9, and 10 are for compound #3.)    -   5) Add 50 μL of RUP3 membranes to all wells in Columns 2 to 10.        (Prior to the start of the assay, the frozen membrane pellets        for both RUP3 and CMV (cells transfected with an expression        plasmid containing no RUP3 sequences), are suspended in binding        buffer, usually 1 ml binding buffer for 1 plate of membranes.        The membranes are kept in ice all the time, and a polytron        (Brinkmann polytron, model # PT-3100) is used (setting 6-7, for        15-20 seconds) to obtain a homogeneous membrane suspension.)        Protein concentration is determined by Bradford protein assay        kit using instructions given in the kit, using the standard        supplied with the kit as a reference. The protein concentration        of the membranes is adjusted with binding buffer, so that 50 μL        membranes=15 ug protein (i.e. 0.3 mg/ml protein).    -   6) In column 1, Wells A, B, C, and D, add 50 μL RUP3 membranes.        To wells E, F, G, and H, add 50 μL CMV membranes, (CMV membranes        being of the same protein concentration as the RUP3 membranes).    -   7) Incubate 1 hour at room temperature with agitation on a        rotating platform shaker. Cover with foil while shaking.    -   8) After 1 hour, add (to all 96 wells), 100 μL of the ¹²⁵I        tracer in detection buffer supplied with the Flashplate kit plus        proclin, made up in the following manner:    -   Pipet per 10 ml per Flashplate: 100 ml of detection buffer+1 ml        ¹²⁵I+0.2 ml of Proclin (the proclin helps to stop the production        of cAMP). Make a smaller quantity of detection buffer mix if you        have fewer plates.    -   9) Shake the plates on a rotating platform shaker for 2 hours,        covering the plates with lead sheeting.    -   10) Seal the plates with the plastic film sealers provided with        the Flashplate kit.    -   11) Count the plates using a TRILUX 1450 Microbeta Counter. See        the door of the counter to determine which counting protocol to        use.    -   12) Data is analyzed on the Arena Database according to the RUP3        non-fusion, IC₅₀ EC₅₀ for 96-well cAMP membrane assay, and the        compound numbers and the concentrations of compounds must be        entered by the user.

B. Membrane Cyclase Criteria

-   -   1) Signal to Noise:        -   An acceptable signal-to-noise ratio for RUP3 can vary from 4            to 6. The raw cpms are approximately 1800 to 2500 for RUP3            and 3500-4500 for CMV. The cpm (or ultimately pmoles of            cAMP/well) cannot be outside the standard curve, and should            not approach well A of the standard curve (50 pmole/well)            and well H (no cAMP). Generally, the pmoles of cAMP produced            by RUP3 receptor are around 11 to 13 pmole/well (for 15            ug/well protein), and for CMV are between 2 to 3 pmole/well            (for 15 ug protein /well).    -   2) Standard curve:        -   The slope should be linear and the error bars for duplicates            should be very small. The receptor and CMV controls cannot            be off scale of the standard curve, as described above. If            the receptor controls are off the high end of the standard            curve,i.e. 50 pmole/well or higher, one must repeat the            experiment using less protein. However, such a case has not            been observed with transiently transfected RUP3 membranes            (10 ug DNA/15 cm plate, using 60 μL Lipofectamine, and            preparing membranes after 24 hour of transfection.)    -   3) The IC₅₀ or EC₅₀ curve should be at 100% (+ or −20%) of        control RUP3 membranes at the top, and should go down to 0 (or        up to 20%) at the bottom. The standard error of the triplicate        determinations should be + or −10%.        C. Stimulation of cAMP in HIT-T15 Cells

HIT-T15 (ATCC CRL#1777) is an immortalized hamster insulin-producingcell line. These cells express RUP3 and therefore can be used to assessthe ability of RUP3 ligands to stimulate or inhibit cAMP accumulationvia its endogenously expressed receptor. In this assay, cells are grownto 80% confluence and then distributed into a 96-well Flashplate (50,000cells/well) for detection of cAMP via a “cAMP Flashplate Assay” (NEN,Cat # SMP004). Briefly, cells are placed into anti-cAMP antibody-coatedwells that contain either vehicle, the test ligand(s) at a concentrationof interest, or 1 uM forskolin. The latter is a direct activator ofadenylyl cyclase and serves as a positive control for stimulation ofcAMP in HIT-T15 cells. All conditions are tested in triplicate. After a1 hour incubation to allow for stimulation of cAMP, a Detection Mixcontaining ¹²⁵I-cAMP is added to each well and the plate is allowed toincubate for another 1 hour. The wells are then aspirated to removeunbound ¹²⁵I-cAMP. Bound ¹²⁵I-cAMP is detected using a Wallac MicrobetaCounter. The amount of cAMP in each sample is determined by comparisonto a standard curve, obtained by placing known concentrations of cAMP insome wells on the plate.

A number of the compounds disclosed herein were screened using the abovedescribed assay. Representative compounds and their corresponding EC₅₀values are shown in the Table 6 below:

TABLE 6 RUP3 (EC₅₀) Compound (μM) A1 0.020 A34 0.027 A35 0.059

D. Stimulation of Insulin Secretion in HIT-T15 Cells

It is known that stimulation of cAMP in HIT-T15 cells causes an increasein insulin secretion when the glucose concentration in the culture mediais changed from 3 mM to 15 mM. Thus, RUP3 ligands can also be tested fortheir ability to stimulate glucose-dependent insulin secretion (GSIS) inHIT-T15 cells. In this assay, 30,000 cells/well in a 12-well plate areincubated in culture media containing 3 mM glucose and no serum for 2hours. The media is then changed; wells receive media containing either3 mM or 15 mM glucose, and in both cases the media contains eithervehicle (DMSO) or RUP3 ligand at a concentration of interest. Some wellsreceive media containing 1 uM forskolin as a positive control. Allconditions are tested in triplicate. Cells are incubated for 30 minutes,and the amount of insulin secreted into the media is determined byELISA, using a kit from either Peninsula Laboratories (Cat # ELIS-7536)or Crystal Chem. Inc. (Cat # 90060).

E. Stimulation of Insulin Secretion in Isolated Rat Islets

As with HIT-T15 cells, it is known that stimulation of cAMP in isolatedrat islets causes an increase in insulin secretion when the glucoseconcentration in the culture media is changed from 60 mg/dl to 300mg/dl. RUP3 is an endogenously expressed GPCR in the insulin-producingcells of rat islets. Thus, RUP3 ligands can also be tested for theirability to stimulate GSIS in rat islet cultures. This assay is performedas follows:

-   -   A. Select 75-150 islet equivalents (IEQ) for each assay        condition using a dissecting microscope. Incubate overnight in        low-glucose culture medium. (Optional.)    -   B. Divide the islets evenly into triplicate samples of 25-40        islet equivalents per sample. Transfer to 40 μm mesh sterile        cell strainers in wells of a 6-well plate with 5 ml of low (60        mg/dl) glucose Krebs-Ringers Buffer (KRB) assay medium.    -   C. Incubate 30 minutes (1 hour if overnight step skipped) at        37° C. and 5% CO₂. Save the supernatants if a positive control        for the RIA is desired.    -   D. Move strainers with islets to new wells with 5 ml/well low        glucose KRB. This is the second pre-incubation and serves to        remove residual or carryover insulin from the culture medium.        Incubate 30 minutes.    -   E. Move strainers to next wells (Low 1) with 4 or 5 ml low        glucose KRB. Incubate @ 37° C. for 30 minutes. Collect        supernatants into low-binding polypropylene tubes pre-labelled        for identification and keep cold.    -   F. Move strainers to high glucose wells (300 mg/dl, which is        equivalent to 16.7 mM). Incubate and collect supernatants as        before. Rinse islets in their strainers in low-glucose to remove        residual insulin. If the rinse if to be collected for analysis,        use one rinse well for each condition (i.e. set of triplicates.)    -   G. Move strainers to final wells with low-glucose assay medium        (Low 2). Incubate and collect supernatants as before.    -   H. Keeping cold, centrifuge supernatants at 1800 rpm for 5        minutes @ 4-8° C. to remove small islets/islet pieces that        escape the 40 mm mesh. Remove all but lower 0.5-1 ml and        distribute in duplicate to pre-labelled low-binding tubes.        Freeze and store at <−20° C. until insulin concentrations can be        determined    -   I. Insulin determinations are done as above, or by Linco Labs as        a custom service, using their rat insulin RIA (Cat. # RI-13K).

Example 2 A. RT-PCR Analysis of RUP3 Expression in Human Tissues (FIG.1A).

RT-PCR was applied to determine the tissue distribution of RUP3.Oligonucleotides used for PCR had the following sequences:

(SEQ ID NO: 3) ZC47: 5′-CATTGCCGGGCTGTGGTTAGTGTC-3′; (forward primer),(SEQ ID NO: 4) ZC48: 5′-GGCATAGATGAGTGGGTTGAGCAG-3′; (reverse primer), 

and the human multiple tissue cDNA panels (MTC, Clontech) were used astemplates (1 ng cDNA per PCR amplification). Twenty-two (22) humantissues were analyzed. PCR was performed using Platinum PCR SuperMix(Life Technologies, Inc.; manufacture instructions were followed) in a50 μl reaction by the following sequences: step 1, 95° C. for 4 min;step 2, 95° C. for 1 min; step 3, 60° C. for 30 sec; step 4, 72° C. for1 min; and step 5, 72° C. for 7 min. Steps 2 through 4 were repeated 35times.

The resulting PCR reactions (15 μl) were loaded on a 1.5% agarose gel toanalyze the RT-PCR products, and a specific 466 base-pair DNA fragmentrepresenting RUP3 was specifically amplified from cDNA of pancreasorigin. Low expression was also evident in subregions of brain.

B. cDNA Dot-Blot Analysis of RUP3 Expression in Human Tissues (FIG. 1B).

Results from RT-PCR analysis were further confirmed in cDNA dot-blotanalysis. In this assay, a dot-blot membrane containing cDNA from 50human tissues (Clontech) was hybridized with a ³²P-radiolabelled DNAprobe having sequences derived from human RUP3. Hybridyzation signalswere seen in pancreas and fetal liver, suggesting these tissues expressRUP3. No significant expression was detected in other tissues analyzed.

C. Analysis of RUP3 by RT-PCR with Isolated Human Pancreatic Islets ofLangerhans (FIG. 1C)

Further analysis of RUP3 by RT-PCR with isolated human pancreatic isletsof Langerhans showed robust expression of RUP3 in islet cells but not incontrol samples.

D. Analysis of RUP3 Expression with cDNAs of Rat Origin by RT-PCR (FIG.1D)

RUP3 expression was further analyzed with cDNAs of rat origin by RT-PCRtechnique. Tissue cDNAs used for this assay were obtained from Clontechexcept those for hypothalamus and islets, which were prepared in house.Concentrations of each cDNA sample were normalized via a control RT-PCRanalysis of the house-keeping gene GAPDH before assaying for RUP3expression. Oligonucleotides used for PCR had the following sequences:

rat RUP3 (“rRUP3”) forward: (SEQ ID NO: 5) 5′-CATGGGCCCTGCACCTTCTTTG-3′;rRUP3 reverse:  (SEQ ID NO: 6) 5′-GCTCCGGATGGCTGATGATAGTGA-3′.PCR was performed using Platinum PCR SuperMix (Life Technologies, Inc.;manufacture instructions were followed) in a 50 μl reaction by thefollowing sequences: step 1, 95° C. for 4 min; step 2, 95° C. for 1 min;step 3, 60° C. for 30 sec; step 4, 72° C. for 1 min; and step 5, 72° C.for 7 min. Steps 2 through 4 were repeated 35 times.

The resulting PCR reactions (15 μl) were loaded on a 1.5% agarose gel toanalyze the RT-PCR products, and a specific 547 base-pair DNA fragmentrepresenting rat RUP3 was specifically amplified from cDNA of pancreasorigin, revealing a similar expression profile with human. Of particularnote, robust expression was seen in isolated islets and hypothalamus.

Example 3 RUP3 Protein Expression is Restricted to p Cell Lineage ofPancreatic Islets (FIG. 2)

A. A polyclonal anti-RUP3 antibody was prepared in rabbits (FIG. 2A).

Rabbits were immunized with an antigenic peptide with sequence derivedfrom rat RUP3 (“rRUP3”). The peptide sequence wasRGPERTRESAYHIVTISHPELDG and shared 100% identity with mouse RUP3 in thecorresponding region. A cysteine residue was incorporated at theN-terminal end of this antigenic peptide to facilitate KLH crosslinkingbefore injecting into rabbits. The resulting antisera (“anti-rRUP3”) andthe corresponding preimmune sera (“pre-rRUP3”) were tested for immunereactivity to mouse RUP3 in immunobloting assays (lanes 1 though 4). Inthis assay, the GST-RUP3 fusion protein was readily recognized by theanti-rRUP3 antisera (lane 4), but not by the preimmune sera (lane 2).The immunoreactive signal could be efficiently eliminated when theimmunobloting assay was performed in the presence of excess antigenicpeptide (lane 6).

B. RUP3 expression in insulin-producing β cells of pancreatic islets(FIG. 2B). Rat pancreas was perfused with 4% paraformaldehyde (PFA) inPBS and embedded in OCT embedding medium. Ten micron sections wereprepared, fixed on glass slides, and immunostained with either pre-rRUP3(FIG. 2B, panel a) or with anti-rRUP3 antisera (FIG. 2B, panels c and e)followed by secondary staining with donkey anti-rabbit IgG conjugated tothe fluorochrome Cy-3. Each section was also co-immunostained with amonoclonal anti-insulin antibody (Santa Cruz, FIG. 2B, panels b and d)in primary staining followed by a secondary staining with donkeyanti-mouse IgG conjugated with FITC, or with a goat anti-glucagonantibody (Santa Cruz, FIG. 2B, panel f) and donkey anti-goat IgG coupledto FITC Immunofluorescent signals were examined under a fluorescentmicroscope. RUP3 was found expressed in insulin producing cells (panelsc and d), but not in glucagons producing cells (panels e and f). Thesedata demonstrated that RUP3 is expressed in β cells but not in β cellsof the rat pancreatic islets. Analogous results were obtained when mousepancreatic sections were investigated for RUP3 expression.

Example 4 Functional Activities of RUP3 In Vitro (FIG. 3)

It was established that RUP3 stimulates the production of cAMP bycotransfection of 293 cells with: (1) a CRE-Luciferase reporter, whereinthe ability to stimulate the production of firefly luciferase depends onincreased cAMP in cells, and (2) an expression plasmid encoding thehuman form of RUP3 (FIG. 3A). Note that cells co-transfected with anexpression plasmid containing no RUP3 sequences (“CMV” in FIG. 3A)produce very little luciferase activity, whereas cells transfected withan expression plasmid encoding RUP3 (“RUP3” in FIG. 3A) have at least a10-fold increase in luciferase activity. This indicates that RUP3stimulates the production of cAMP when introduced into 293 cells. Thisproperty of RUP3 is conserved across species, because hamster RUP3stimulates luciferase activity when introduced into 293 cells in amanner analogous to that described for human RUP3 (FIG. 3B).

It is established that, when cAMP is increased in insulin-producingcells of the pancreas, these cells exhibit an enhanced ability tosecrete insulin when glucose concentrations rise. To test whether RUP3might impart enhanced glucose-dependent insulin release, retroviruscontaining human RUP3 was used to generate Tu6 cells that express highlevels of RUP3. Tu6 cells produce insulin, but do not expressappreciable levels of RUP3 and do not normally exhibit an increase ininsulin release when increased glucose is present in the culture media.As shown in FIG. 3C, Tu6 cells transduced with a control virus thatcontains no receptor are still able to produce insulin, but do not showan increase in insulin secretion when the concentration of glucose inthe culture media is shifted from 1 mM to 16 mM. By contrast, Tu6 cellstransduced with RUP3-containing retrovirus display significantglucose-dependent insulin secretion (FIG. 3C).

Example 5 In Vivo Effects of RUP3 Agonists on Glucose Homeostasis inRats

A. Oral Glucose Tolerance Test (oGTT)

Male Sprague Dawley rats weighing approximately 200 g-250 g were fastedfor 15 hours and randomly grouped (n=6) to receive a RUP3 agonist(Compounds A78, A88 or A118) at 3, 10 or 30 mg/kg. Compounds weredelivered orally via a gavage needle (p.o., volume 3 ml/kg). At time 0,levels of blood glucose were assessed using a glucometer (Elite XL,Bayer), and rats were administered either vehicle (20%hydroxypropyl-beta-cyclodextrin) or test compound. Thirty minutes afteradministration of test compound, levels of blood glucose were againassessed, and rats were administered dextrose orally at a dose of 2g/kg. Blood glucose measurements were then taken 30 min, 60 min, and 120min after this time. Table 7 shows the mean percentage inhibition ofglucose excursion for each test compound, averaged across the sixanimals in the treatment group. These results demonstrated that the RUP3agonists, Compounds A78, A88 and A118 lowered blood glucose afterchallenge with glucose.

TABLE 7 Mean % Inhibition of Glucose Excursion Compound % inhibition ofglucose excursion, (dose, mg/kg) A78 39%, (10) A88 38%, (30) A118 43%,(30)

Example 6 Generation of Tu6/RUP3 Stable Lines

To produce Tu6 cells that express RUP3 at high levels, a retrovirusbearing an expression cassette for RUP3 was generated. Briefly, RUP3coding sequence was cloned into the retroviral vector pLNCX2 (Clontech,Cat tt 6102-1). The amphotropic packaging cell line PT-67 (Clontech™,K1060-D) was then transfected with either the parental vector pLNCX2 orpLNCX2/RUP3 using Lipofectamine and stable lines were established usingguidelines provided by the PT-67 vendor. Retrovirus-containingsupernatant was obtained by collecting media from the resultant stablesaccording to the manufacturer's directions. Tu6 cells, in a 10 cm dish,were then infected with retrovirus by incubating in a solution of 1 mlviral supernatant/9 ml culture media containing 40 ug/ml polybrene for24 hours. The medium was then changed to culture media containing 300ug/ml G418. G418-resistant clones were ultimately created by virtue ofthe neomycin-resistance gene cassette present in the pLNCX2 vector, thusindicating the successful integration of retrovirus into the Tu6 genome.The expression of RUP3 in the Tu6/RUP3 G418-resistant colonies wasconfirmed by Northern blot.

Example 7 Insulin Secretion, Tu6 Stables

To measure insulin secretion from rodent insulin-producing cell lines,cells were first cultured overnight in serum-free, glucose-deficientmedia. The following morning, the cells were then placed in the samemedia supplemented with either 1 mM or 16 mM glucose. After anincubation of 4 hours, the media was collected and analyzed for insulincontent using a Rat Insulin Enzyme-Immunoassay (EIA) System (AmershamPharmacia Biotech, Cat. tt RPN 2567). Typically, the assay was performedusing multiple dilutions of sample media in order to ensure that thesample measurements fell within the boundaries of the standard curve(generated using known amounts of insulin), as recommended by themanufacturer.

Example 8 Receptor Binding Assay

In addition to the methods described herein, another means forevaluating a test compound is by determining binding affinities to theRUP3 receptor. This type of assay generally requires a radiolabelledligand to the RUP3 receptor. Absent the use of known ligands for theRUP3 receptor and radiolabels thereof, compounds of Formula (I) can belabelled with a radioisotope and used in an assay for evaluating theaffinity of a test compound to the RUP3 receptor.

A radiolabelled RUP3 compound of Formula (I) can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radiolabelledcompound of Formula (I)” to the RUP3 receptor. Accordingly, the abilityto compete with the “radio-labelled compound of Formula (I)” orRadiolabelled RUP3 Ligand for the binding to the RUP3 receptor directlycorrelates to its binding affinity of the test compound to the RUP3receptor.

Assay Protocol for Determining Receptor Binding for RUP3:

A. RUP3 Receptor Preparation

293 cells (human kidney, ATCC), transiently transfected with 10 ug humanRUP3 receptor and 60 μL Lipofectamine (per 15-cm dish), were grown inthe dish for 24 hours (75% confluency) with a media change and removedwith 10 ml/dish of Hepes-EDTA buffer (20 mM Hepes+10 mM EDTA, pH 7.4).The cells were then centrifuged in a Beckman Coulter centrifuge for 20minutes, 17,000 rpm (JA-25.50 rotor). Subsequently, the pellet wasresuspended in 20 mM Hepes+1 mM EDTA, pH 7.4 and homogenized with a50-ml Dounce homogenizer and again centrifuged. After removing thesupernatant, the pellets were stored at −80° C., until used in bindingassay. When used in the assay, membranes were thawed on ice for 20minutes and then 10 mL of incubation buffer (20 mM Hepes, 1 mM MgCl₂,100 mM NaCl, pH 7.4) added. The membranes were then vortexed toresuspend the crude membrane pellet and homogenized with a BrinkmannPT-3100 Polytron homogenizer for 15 seconds at setting 6. Theconcentration of membrane protein was determined using the BRL Bradfordprotein assay.

B. Binding Assay

For total binding, a total volume of 50 μL of appropriately dilutedmembranes (diluted in assay buffer containing 50 mM Tris HCl (pH 7.4),10 mM MgCl₂, and 1 mM EDTA; 5-50 μg protein) is added to 96-wellpolyproylene microtiter plates followed by addition of 100 ut of assaybuffer and 50 μL of Radiolabelled RUP3 Ligand. For nonspecific binding,50 μL of assay buffer is added instead of 100 μL and an additional 50 μLof 10 μM cold RUP3 is added before 50 μL of Radiolabelled RUP3 Ligand isadded. Plates are then incubated at room temperature for 60-120 minutes.The binding reaction is terminated by filtering assay plates through aMicroplate Devices GF/C Unifilter filtration plate with a Brandell96-well plate harvestor followed by washing with cold 50 mM Tris HCl, pH7.4 containing 0.9% NaCl. Then, the bottom of the filtration plate aresealed, 50 μL of Optiphase Supermix is added to each well, the top ofthe plates are sealed, and plates are counted in a Trilux MicroBetascintillation counter. For compound competition studies, instead ofadding 100 ut of assay buffer, 100 ut of appropriately diluted testcompound is added to appropriate wells followed by addition of 50 ut ofRadiolabelled RUP3 Ligand.

C. Calculations

The test compounds are initially assayed at 1 and 0.1 μM and then at arange of concentrations chosen such that the middle dose would causeabout 50% inhibition of a Radio-RUP3 Ligand binding (i.e., IC₅₀).Specific binding in the absence of test compound (B_(O)) is thedifference of total binding (B_(T)) minus non-specific binding (NSB) andsimilarly specific binding (in the presence of test compound) (B) is thedifference of displacement binding (B_(D)) minus non-specific binding(NSB). IC₅₀ is determined from an inhibition response curve, logit-logplot of % B/B_(O) vs concentration of test compound.

K_(i) is calculated by the Cheng and Prustoff transformation:

K _(i) =IC ₅₀/(1+[L]/K _(D))

where [L] is the concentration of a Radio-RUP3 Ligand used in the assayand K_(D) is the dissociation constant of a Radio-RUP3 Ligand determinedindependently under the same binding conditions.

Chemistry Syntheses of Compounds of the Present Invention Example 9

The compounds of the invention and their synthesis are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to the CS Chem Draw UltraVersion 7.0.1, AutoNom version 2.2. In certain instances common namesare used and it is understood that these common names would berecognized by those skilled in the art.

Chemistry: Proton nuclear magnetic resonance (¹H NMR) spectra wererecorded on a Varian Mercury Vx-400 equipped with a 4 nucleus autoswitchable probe and z-gradient or a Bruker Avance-400 equipped with aQNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient.Chemical shifts are given in parts per million (ppm) with the residualsolvent signal used as reference. NMR abbreviations are used as follows:s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad.Microwave irradiations were carried out using the Emyrs Synthesizer(Personal Chemistry). Thin-layer chromatography (TLC) was performed onsilica gel 60 F₂₅₄ (Merck), preparatory thin-layer chromatography (prepTLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman), andcolumn chromatography was carried out on a silica gel column usingKieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done in vacuo on aBuchi rotary evaporator. Celite 545® was used during palladiumfiltrations.

LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; HPLC system controller:SCL-10A VP, Shimadzu Inc. UV-Detector: SPD-10A VP, Shimadzu Inc;Autosampler: 215 Liquid Handler, Gilson Inc; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex Software: Masschrom1.5.2.

Example 9.1 Preparation of4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A1)

4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.03 mmol, 610mg) and sodium hydride (10.6 mmol, 255 mg) were dissolved in dry THF (20mL) and stirred for 30 minutes at room temperature. Then,(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (3.03mmol, 1.0 g) was added. The reaction was stirred at room temperature for30 minutes. Its progress was monitored by thin layer chromatography andLCMS. Sodium hydride was quenched with water and the desired compoundwas extracted in ethyl acetate. Organic solvents were evaporated invacuo. Flash chromatography (Silica gel 60; 30/70 EtOAc/Hexanes)provided Compound A1 as a yellow solid (1.2 g, 68%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 10.10 (s, 1H), 8.33 (s, 1H), 7.90 (d, 2H), 7.79 (d, 2H),5.51 (heptet, 1H), 3.58 (m, 2H), 3.46 (m, 2H), 2.97 (s, 3H), 1.84 (m,4H), 1.36 (s, 9H). LCMS (ESI), m/z 494.4 (M+H+, 100%).

Example 9.2 Preparation of(4-Methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(Compound A2)

Compound A1 (1.42 mmol, 700 mg) was dissolved in a commerciallyavailable 4M HCl solution in 1,4-dioxane (25 mL). The mixture wasstirred at 40° C. for 1.0 hour. Removal of organic solvents in vacuoprovided compound A2 as a yellow solid (580 mg, 100%). ¹H NMR (400 MHz,MeOH-d₄) δ (ppm): 8.29 (s, 1H), 7.81 (quartet, 4H), 5.56 (m, 1H), 3.21(m, 4H), 3.00 (s, 3H), 2.07 (m, 4H). LCMS (ESI), m/z 394.1 (M+H+, 100%).

Example 9.3 Preparation of1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-1-one(Compound A3)

Compound A2 (0.12 mmol, 50 mg), 3,3-dimethyl-butyryl chloride (0.18mmol, 24 mg) and triethylamine (0.63 mmol, 88 L) were dissolved in DMFand microwaved at 80° C. for 5 minutes. The reaction mixture wasquenched with water and extracted with ethyl acetate. Removal of organicsolvents in vacuo provided Compound A3 as a yellow solid (46 mg, 78%).¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.98 (s, 1H), 8.20 (s, 1H), 7.77 (d,2H), 7.64 (d, 2H), 5.44 (heptet, 1H), 3.71 (m, 1H), 3.48 (m, 3H), 2.75(s, 3H), 2.11 (quartet, 2H), 1.76 (m, 4H), 0.85 (s, 9H). LCMS (ESI), m/z492.4 (M+H+, 100%).

Example 9.4 Preparation of(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-thiophen-3-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]-thiophen-3-ylmethyl-amine(Compound A4)

Compound A2 (0.12 mmol, 50 mg), 3-chloromethyl-thiophene (0.12 mmol, 16mg) and triethylamine (0.63 mmol, 88 pt) were dissolved in DMF andmicrowaved at 80° C. for 10 minutes. The reaction mixture was quenchedwith water and extracted with ethyl acetate. Purification by HPLCprovided Compound A4 as a yellow solid (24 mg, 34%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 8.35 (s, 1H), 7.93 (m, 2H), 7.79 (m, 2H), 7.22 (m, 1H),7.19 (m, 2H), 7.08 (m, 1H), 6.98 (m, 1H), 6.84 (m, 1H), 5.68 (m, 1H),4.08 (m, 4H), 3.36 (m, 2H), 3.04 (s, 3H), 2.86 (m, 2H), 2.34 (m, 2H),2.07 (m, 2H). LCMS (ESI), m/z 586.1 (M+H+, 100%).

Example 9.5 Preparation of(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-pyridin-2-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]amine(Compound A5)

Compound A2 (0.12 mmol, 50 mg), 2-chloromethyl-pyridine (0.12 mmol, 20mg) and triethylamine (0.63 mmol, 88 pt) were dissolved in DMF andmicrowaved at 80° C. for 10 minutes. The reaction mixture was quenchedwith water and extracted with ethyl acetate. Removal of organic solventin vacuo provided Compound A5 pure as a yellow solid (27 mg, 47%). ¹HNMR (400 MHz, CDCl₃) δ (ppm): 10.09 (s, 1H), 8.51 (m, 1H), 8.32 (s, 1H),7.89 (d, 2H), 7.78 (d, 2H), 7.60 (t, 1H), 7.36 (m, 1H), 7.13 (t, 1H),5.40 (m, 1H), 3.65 (m, 2H), 3.07 (s, 3H), 2.72 (m, 2H), 2.45 (m, 2H),2.02 (m, 2H), 1.91 (m, 2H). LCMS (ESI), m/z 484.5 (M+H+, 100%).

Example 9.6 Preparation of(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]amine(Compound A6)

Compound A2 (0.12 mmol, 50 mg), 3-chloromethyl-pyridine (0.12 mmol, 20mg) and triethylamine (0.63 mmol, 88 pt) were dissolved in DMF andmicrowaved at 80° C. for 10 minutes. The reaction mixture was quenchedwith water and extracted with ethyl acetate. Removal of organic solventin vacuo provided Compound A6 pure as a yellow solid (39 mg, 66%). ¹HNMR (400 MHz, CDCl₃) δ (ppm): 10.09 (s, 1H), 8.45 (m, 2H), 8.33 (s, 1H),7.90 (d, 2H), 7.78 (d, 2H), 7.65 (m, 1H), 7.21 (m, 1H), 5.41 (heptet,1H), 3.52 (m, 2H), 3.01 (s, 3H), 2.65 (m, 2H), 2.47 (m, 2H), 1.98 (m,2H), 1.94 (m, 2H). LCMS (ESI), m/z 484.3 (M+H+, 100%).

Example 9.7 Preparation of{6-[1-(3,3-Dimethyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine(Compound A7)

Compound A2 (0.20 mmol, 80 mg), and 3,3-dimethyl-butyraldehyde (0.24mmol, 30 pt) were dissolved in methanol (2 mL) and stirred for 5 minutesat room temperature. Then, added sodium borohydride (0.25 mmol, 8.7 mg)and stirred for 10 minutes at room temperature. The reaction mixture wasquenched with saturated ammonium chloride solution (1 mL) followed by anextraction with dichloromethane. Removal of organic solvent in vacuo andpurification by prep-LCMS provided Compound A7 as a yellow solid (12 mg,13%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.17 (s, 1H), 8.36 (s, 1H), 7.90(d, 2H), 7.78 (d, 2H), 5.71 (s broad, 1H), 3.51 (d, 2H), 3.08 (m, 2H),2.97 (m, 5H), 2.38 (m, 2H), 2.14 (m, 2H), 1.60 (m, 2H), 0.85 (s, 9H).LCMS (ESI), m/z 478.3 (M+H+, 100%).

Example 9.8 Preparation of(4-Methanesulfonyl-phenyl)-{6-[1-(3-methyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-amine(Compound A8)

Compound A2 (0.15 mmol, 60 mg), and 3-methyl-butyraldehyde (0.15 mmol,13 mg) were dissolved in methanol (2 mL) and stirred for 5 minutes atroom temperature. Then, sodium borohydride (0.18 mmol, 6.3 mg) was addedat 0° C. The reaction was complete immediately upon addition of sodiumborohydride. The mixture was quenched with saturated ammonium chloridesolution (1 mL) followed by an extraction with dichloromethane. Removalof organic solvent in vacuo and purification by HPLC provided CompoundA8 as a yellow solid (25 mg, 36%). ¹H NMR (400 MHz, CDCl₃) δ (ppm):10.17 (s, 1H), 8.35 (s, 1H), 7.90 (d, 2H), 7.80 (d, 2H), 5.72 (s broad,1H), 3.65 (m, 2H), 3.11 (m, 2H), 2.96 (m, 5H), 2.40 (m, 2H), 2.15 (m,2H), 1.60 (m, 3H), 0.85 (d, 6H). LCMS (ESI), m/z 464.4 (M+H+, 100%).

Example 9.9 Preparation of(4-Methanesulfonyl-phenyl)-[5-nitro-6-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy)-pyrimidin-4-yl]-amine(Compound A9)

Compound A2 (0.13 mmol, 50 mg), and 2-bromo-pyridine (0.53 mmol, 53 μL)were dissolved in DMF (1 mL) and triethylamine (0.46 mmol, 63 pt). Thereaction was heated in a microwave at 165° C. for 40 minutes. Themixture was quenched with water and extracted with ethyl acetate.Removal of organic solvent in vacuo and purification by prep-TLCprovided Compound A9 as a yellow solid (12 mg, 20%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 10.10 (s, 1H), 8.35 (s, 1H), 8.13 (m, 1H), 7.89 (d, 2H),7.81 (d, 2H), 7.42 (m, 1H), 6.64 (d, 1H), 6.55 (m, 1H), 5.58 (heptet,1H), 3.78 (m, 2H), 3.60 (m, 2H), 3.00 (s, 3H), 2.02 (m, 2H), 1.91 (m,2H). LCMS (ESI), m/z 471.4 (M+H+, 100%).

Example 9.10 Preparation of4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester (Compound A10)

Compound A2 (0.13 mmol, 50 mg), and ethyl chloroformate (0.13 mmol, 13pt) were dissolved in DMF (1 mL) and triethylamine (0.36 mmol, 50 pt).The reaction was heated in a microwave at 80° C. for 4 minutes. Themixture was quenched with water and extracted with ethyl acetate.Removal of organic solvent in vacuo provided Compound A10 as a yellowsolid (50 mg, 89%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.97 (s, 1H), 8.20(s, 1H), 7.77 (d, 2H), 7.66 (d, 2H), 5.41 (heptet, 1H), 3.96 (q, 2H),3.47 (m, 4H), 2.88 (s, 3H), 1.72 (m, 4H), 1.08 (t, 3H). LCMS (ESI), m/z466.3 (M+H+, 100%).

Example 9.11 Preparation of1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one(Compound A11)

Compound A2 (0.12 mmol, 50 mg), and 1-bromo-3,3-dimethyl-butan-2-one(0.12 mmol, 16 μL) were dissolved in DMF (1 mL) and triethylamine (0.36mmol, 50 μL). The reaction was heated in a microwave at 80° C. for 4minutes. The mixture was quenched with water and extracted with ethylacetate. Removal of organic solvent in vacuo and purification by HPLCprovided Compound All as a yellow solid (15 mg, 25%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 10.11 (s, 1H), 8.32 (s, 1H), 7.89 (d, 2H), 7.78 (d, 2H),5.49 (s broad, 1H), 3.53 (s broad, 2H), 3.01 (s, 3H), 2.78 (m, 4H), 2.18(m, 2H), 1.96 (m, 2H), 1.20 (s, 9H). LCMS (ESI), m/z 492.3 (M+H+, 100%).

Example 9.12 Preparation of{6-[1-(2-Ethoxy-ethyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine(Compound A12)

Compound A2 (0.13 mmol, 50 mg), and 1-bromo-2-ethoxy-ethane (0.65 mmol,99 mg) were dissolved in DMF (1 mL) and triethylamine (0.91 mmol, 127μL). The reaction was heated in a microwave at 80° C. for 20 minutes.The mixture was quenched with water and extracted with ethyl acetate.Removal of organic solvent in vacuo and purification by prep-TLCprovided Compound A12 as a yellow solid (20 mg, 33%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 10.06 (s, 1H), 8.29 (s, 1H), 7.84 (d, 2H), 7.74 (d, 2H),5.39 (s broad, 1H), 3.53 (m, 2H), 3.39 (q, 2H), 2.86 (s, 3H), 2.77 (m,2H), 2.65 (m, 3H), 2.04 (m, 2H), 1.92 (m, 3H), 1.09 (m 3H). LCMS (ESI),m/z 466.3 (M+H+, 100%).

Example 9.13 Preparation of4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester (Compound A13)

4-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 mmol,226 mg) and sodium hydride (1.0 mmol, 25 mg) were dissolved in dimethylacetamide (1.0 mL) and stirred for 30 minutes at room temperature. Then,(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.21mmol, 70 mg) was added. The reaction was stirred at 70° C. for 20minutes and the progress of the reaction was monitored by thin layerchromatography and LCMS. Sodium hydride was quenched with water and thedesired compound was extracted in ethyl acetate. Organic solvents wereevaporated in vacuo. Flash chromatography (Silica gel 60; 40/60EtOAc/Hexanes) provided Compound A13 as a yellow solid (10 mg, 10%). ¹HNMR (400 MHz, CDCl₃) δ (ppm): 10.21 (s, 1H), 8.41 (s, 1H), 7.97 (d, 2H),7.86 (d, 2H), 4.39 (d, 2H), 4.17 (m, 2H), 3.07 (s, 3H), 2.76 (m, 2H),1.83 (m, 2H), 1.59 (m, 1H), 1.45 (s, 9H), 1.30 (m, 2H). LCMS (ESI), m/z408.2 (M+H+, 100%).

Example 9.14 Preparation of4-{2-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (Compound A14)

4-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0mmol, 230 μL) and sodium hydride (1.0 mmol, 26 mg) were dissolved indimethyl acetamide (1.0 mL) and stirred for 30 minutes at roomtemperature. Then,(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.21mmol, 70 mg) was added. The reaction was stirred at 70° C. for 20minutes. Its progress was monitored by thin layer chromatography andLCMS. Sodium hydride was quenched with water and the desired compoundwas extracted in ethyl acetate. Organic solvents were evaporated invacuo. Flash chromatography (Silica gel 60; 40/60 EtoAc/Hexanes)provided Compound A14 as a yellow oil (90 mg, 82%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 10.26 (s, 1H), 8.40 (s, 1H), 7.98 (d, 2H), 7.86 (d, 2H),4.51 (t, 2H), 4.09 (m, 2H), 3.73 (t, 2H), 3.07 (s, 3H), 2.72 (m, 2H),1.76 (m, 1H), 1.55 (q, 2H), 1.46 (s, 9H), 1.15 (m, 2H). LCMS (ESI), m/z422.2 (M+H+, 100%).

Example 9.15 Preparation of3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester (Compound A15)

3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 mmol, 197mg) and sodium hydride (1.0 mmol, 26 mg) were dissolved in THF (1.5 mL)and stirred for 30 minutes at room temperature. Then,(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.21mmol, 70 mg) was added. The reaction was stirred at 0° C. for 30minutes. Its progress was monitored by thin layer chromatography andLCMS. Sodium hydride was quenched with water and the desired compoundwas extracted in ethyl acetate. Organic solvents were evaporated invacuo. Flash chromatography (Silica gel 60; 50/50 EtOAc/Hexanes)provided Compound A15 as a yellow oil (60 mg, 60%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 10.18 (s, 1H), 8.47 (s, 1H), 7.98 (d, 2H), 5.78 (m, 2H),5.78 (m, 1H), 4.46 (m, 2H), 3.08 (s, 3H), 2.26 (m, 2H), 1.63 (m, 2H),1.48 (s, 9H). LCMS (ESI), m/z 480.4 (M+H+, 100%).

Example 9.16 Preparation of3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (Compound A16)

3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.65mmol, 131 mg) and sodium hydride (1.3 mmol, 31 mg) were dissolved inN,N-dimethyl acetamide (1.5 mL) and stirred for 30 minutes at roomtemperature. Then,(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.26mmol, 84 mg) was added. The reaction was stirred at 70° C. for 30minutes. Its progress was monitored by thin layer chromatography andLCMS. Sodium hydride was quenched with water and the desired compoundwas extracted in ethyl acetate. Organic solvents were evaporated invacuo. Flash chromatography (Silica gel 60; 50/50 EtoAc/Hexanes)provided Compound A16 as a yellow solid (96 mg, 54%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 10.21 (s, 1H), 8.41 (s, 1H), 7.97 (d, 2H), 7.86 (d, 2H),4.52 (m, 2H), 3.49 (m, 2H), 3.11 (s, 3H), 2.75 (m, 1H), 1.84 (m, 2H),1.65 (m, 2H), 1.46 (s, 9H). LCMS (ESI), m/z 394.1 (M+H+, 100%).

Example 9.17 Preparation of3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (Compound A17)

(S)-3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.65mmol, 131 mg) and sodium hydride (1.3 mmol, 31 mg) were dissolved inN,N-dimethyl acetamide (1.5 mL) and stirred for 30 minutes at roomtemperature. Then,(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.26mmol, 84 mg) was added. The reaction was stirred at 70° C. for 30minutes. Its progress was monitored by thin layer chromatography andLCMS. Sodium hydride was quenched with water and the desired compoundwas extracted in ethyl acetate. Organic solvents were evaporated invacuo. Flash chromatography (Silica gel 60; 50/50 EtoAc/Hexanes)provided Compound A17 as a yellow solid (26 mg, 15%). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 10.22 (s, 1H), 8.41 (s, 1H), 7.97 (d, 2H), 7.87 (d, 2H),4.52 (m, 2H), 3.49 (m, 2H), 3.09 (s, 3H), 2.75 (m, 1H), 1.97 (m, 2H),1.67 (m, 2H), 1.49 (s, 9H). LCMS (ESI), m/z 394.1 (M+H+, 100%).

Example 9.18 Preparation of4-[5-Cyano-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A18)

To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester(304 mg, 1.51 mmol) in DMF was added sodium hydride (36 mg, 1.51 mmol)and allowed the resulting mixture was allowed to stir at roomtemperature. After 30 minutes,4-chloro-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrilewas added and the resulting mixture was heated at 70° C. for 1 hour.Worked up with Ethyl acetate, sodium bicarbonate, dried with magnesiumsulfate and evaporated to afford a white solid as Compound A18 (80.0 mg,59.8%). ¹H NMR 400 MHz DMSO-d₆ δ (ppm): 9.90 (s, 1H), 8.54 (d, 1H), 8.40(s, 1H, pyrimidine), 7.78 (m, 1H), 7.29 (d, 1H), 5.75 (s, 3H), 5.35 (m,1H), 3.58 (m, 2H), 3.27 (m, 2H), 1.93 (m, 2H), 1.63 (m, 2H), 1.38 (s,9H), LCMS (ESI) for C₂₁H₂₆ClN₆OS: m/z 443.4 (M+H⁺, 100%).

The intermediate4-chloro-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrilewas prepared in the following manner:

A. 4,6-Dichloro-pyrimidine-5-carbaldehyde

Phosphorus oxychloride (200 mL, 2184.8 mmol) was added drop wise (viaadditional funnel) to DMF cooled to 0° C. After for 1 hour, 4,6dihydroxypyridimidine (50.0 g, 446.1 mmol) was added and the mixture wasallowed to warm to room temperature. The resulting heterogeneous mixturewas refluxed for 3 hours. The volatiles were removed at reduce pressure,and the residue was poured in ice water and extract with CHCl₃/Et₂O,wash with sodium bicarbonate and concentrate under high vacuum. Finalproduct was purified by silica plug using CH₂Cl₂ to afford a yellowsolid (54.0 g), ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.3 (s, 1H, aldehyde),8.7 (s, 1H, pyrimidine).

B. 4,6-Dichloro-pyrimidine-5-carbonitrile

4,6-Dichloro-pyrimidine-5-carbaldehyde (15.0 g, 84.75 mmol, 1.0equivalent) was dissolved in ethyl acetate (150 mL), mixed withhydroxylamine hydrochloride in water (30 mL) and added sodium acetate.Reaction was at left room temperature for 1.5 hours. Worked up withethyl acetate, sodium bicarbonate, dried with magnesium sulfate,rotovaped and dried and high vacuum to afford a white solid (14.593 g).The white solid (iminohydroxy intermediate) was added to thionylchloride (100 mL) at 0° C. with stirring and allowed to warm to roomtemperature for 3 hours. The reaction was quenched in ice (500 g), andthe precipitated was filtered off, washed with cold water, and driedunder high vacuum to afford a white solid as product (10.739 g, 72.8%).¹H NMR 400 MHz CDCl₃ δ (ppm): 8.95 (s, 1H, pyrimidine).

C.4-Chloro-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile

6-Methylsulfanyl-pyridin-3-ylamine (500.0 mg, 3.57 mmol, 1.0 equivalent)in DMF (1 mL) was added drop wise to a suspension of4,6-dichloro-pyrimidine-5-carbonitrile (616.9 mg, 3.57 mmol, 1.0equivalent), potassium carbonate (542.1 mg, 3.92 mmol, 1.1 equivalent)at 0° C. under stirring. The reaction was left reacting at roomtemperature for 1.5 hours. Product was crystallized using ethyl acetate,hexane getting a yellow solid as product (650.00 mg, 65.62%). LCMS (ESI)for C₁₁H₈ClN₅S: m/z 278.0 (M+H⁺, 100%).

Example 9.19 Preparation of4-[5-Cyano-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A19)

To a solution of Compound A18 (52.0 mg, 0.11 mmol) in CH₂Cl₂ (5 mL) wasadded mCPBA (101.5 mg, 0.59 mmol) and the resulting mixture was heatedto reflux. After 30 minutes, the mixture was worked up with water (basicconditions using ammonium hydroxide, pH=10), dichloromethane, and sodiumbicarbonate, dried with magnesium sulfate and evaporated to affordCompound A19 as a white solid (24.9 mg, 43.9%). ¹H NMR 400 MHz CDCl₃ δ(ppm): 8.92 (d, 1H), 8.52 (d, 1H), 8.46 (s, 1H, pyrimidine), 8.10 (d,1H), 7.47 (s, 1H), 5.45 (m, 1H), 3.77 (m, 2H), 3.37 (m, 2H), 3.24 (m,3H), 1.98 (m, 2H), 1.84 (m, 2H), 1.48 (s, 9H), LCMS (ESI) forC₂₁H₂₆ClN₆OS: m/z 474.9 (M+H⁺, 100%).

Example 9.20 Preparation of[6-(1-Hexyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine(Compound A20)

General procedure; alkoxide substitution of(6-Chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine. In a16 mL reaction vial was placed sodium hydride (25 mg, 60% in oil, 0.625mmol) and 1.5 mL of THF. 1-Hexyl-piperidin-4-ol (30 mg, 0.162 mmol) wasadded to the suspension and the mixture was stirred for 20 min under N₂at room temperature, followed by the addition of(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (41mg, 0.125 mmol). After stirring overnight under N₂ at room temperature,all of the starting chloropyrimidines was completely converted asindicated by LCMS. The reaction mixture was then concentrated undervacuum and purified by preparative HPLC to give Compound A20. ¹ H NMR(CDCl₃, 400 MHz) δ 0.89 (m, 2H), 1.37 (m, 6H), 1.80 (m, 2H), 2.21 (m,2H), 2.56 (m, 2H), 3.03 (m, 2H), 3.08 (s, 3H), 3.18 (m, 2H), 3.56 (m,2H), 5.79 (m, 1H), 7.86 (d, 2H), 7.98 (d, 2H), 8.40 (s, 1H), 10.23 (s,1H), 12.5 (s, 1H). Exact mass calculated for C₂₂H₃₁N₅O₅S 477.20, found478.4 (MH⁺).

Example 9.21 Preparation of[6-(1-Cyclopropylmethyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine(Compound A21)

Compound A21 was prepared in a similar manner as described above usingN-cyclopropanyl-4-hydroxy-piperidine. ¹H NMR (CDCl₃, 400 MHz) δ 0.43 (m,2H), 0.82 (m, 2H), 1.18 (m, 1H), 2.26 (m, 2H), 2.56 (m, 2H), 3.01 (m,2H), 3.08 (s, 3H), 3.25 (m, 2H), 3.69 (m, 2H), 5.80 (m, 1H), 7.87 (d,2H), 7.97 (d, 2H), 8.44 (s, 1H), 10.24 (s, 1H), 12.0 (s, 1H). Exact masscalculated for C₂₀H₂₅N₅O₅S 447.16, found 448.3 (MH⁺).

Example 9.22 Preparation of4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A22)

General procedure for the syntheses of carbamates, pyridinamides, andsulfonamides.

In a 16 mL reaction vessel was placed(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (42 mg, 0.1 mmol), triethylamine (900 and DMF (1.5mL) was added to completely dissolve the solid material. Isopropylchloroformate (0.15 mL, 1.0M in toluene) was added to the solution andthe mixture was stirred 30 min under N₂ at room temperature. After allof the starting amine was completely converted as indicated by LCMS, thereaction was stopped by quenching with water. The reaction mixture wasconcentrated under vacuum and purified by preparative HPLC to giveCompound A22, ¹H NMR (CDCl₃, 400 MHz) δ 1.26 (d, 6H), 1.89 (m, 2H), 1.93(m, 2H), 3.07 (s, 3H), 3.63 (m, 2H), 3.67 (m, 2H), 4.94 (m, 1H), 5.61(m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.40 (s, 1H), 10.18 (s, 1H). Exactmass calculated for C₂₀H₂₅N₅O₇S 479.15, found 480.4 (MH⁺).

Example 9.23 Preparation of4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-isopropyl-5-methyl-cyclohexyl ester (Compound A23)

Compound A23 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (500, menthylchloroformate (10 mg, 0.046 mmol), DMF (0.6 mL), ¹H NMR (CDCl₃, 400 MHz)δ 0.81 (d, 3H), 0.92 (d, 6H), 1.06 (m, 1H), 1.10 (m, 1H), 1.41 (m, 1H),1.51 (m, 1H), 1.67 (m, 2H), 1.94 (m, 4H), 2.08 (m, 2H), 3.08 (s, 3H),3.65 (m, 4H), 4.58 (m, 1H), 5.60 (m, 1H), 7.86 (d, 2H), 7.97 (d, 2H),8.41 (s, 1H), 10.18 (s, 1H). Exact mass calculated for C₂₇H₃₇N₅O₇S575.24, found 576.4 (MH⁺).

Example 9.24 Preparation of{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-3-yl-methanone(Compound A24)

Compound A24 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (16 mg, 0.037 mmol), triethylamine (50 μl),nicotinoyl chloride (10 mg, 0.046 mmol), DMF (1 mL), ¹H NMR (CDCl₃, 400MHz) δ 1.95 (m, 2H), 2.14 (m, 2H), 3.07 (s, 3H), 3.55 (m, 1H), 3.65 (m,2H), 4.13 (m, 1H), 5.72 (m, 1H), 7.40 (m, 1H), 7.79 (m, 1H), 7.87 (d,2H), 7.97 (d, 2H), 8.41 (s, 1H), 8.70 (m, 2H), 10.20 (s, 1H). Exact masscalculated for C₂₂H₂₂N₆O₆S 498.13, found 499.3 (MH⁺).

Example 9.25 Preparation of(2-Chloro-pyridin-3-yl)-{4-[6-(4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone(Compound A25)

Compound A25 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (16 mg, 0.037 mmol), triethylamine(500,2-chloro-nicotinoyl chloride (1.0 mg, 0.046 mmol), DMF (1 mL), ¹HNMR (CDCl₃, 400 MHz) δ 1.91 (m, 1H), 2.00 (m, 1H), 2.14 (m, 2H), 3.08(s, 3H), 3.36 (m, 1H), 3.65 (m, 2H), 4.13 (m, 1H), 4.31 (m, 1H), 5.72(m, 1H), 7.36 (m, 1H), 7.69 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41(m, 1H), 8.47 (m, 1H), 10.20 (s, 1H). Exact mass calculated forC₂₂H₂₁ClN₆O₆S 532.09, found 533.3 (MH⁺).

Example 9.26 Preparation of{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-2-yl-methanone(Compound A26)

Compound A26 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (16 mg, 0.037 mmol), triethylamine (500,pyridine-2-carbonyl chloride (10 mg, 0.046 mmol)[Pyridine-2-carbonylchloride was prepared by refluxing picolinic acid with SOCl₂ for 3 hoursand worked up in general method], DMF (1 mL), ¹H NMR (CDCl₃, 400 MHz) δ1.95 (m, 2H), 2.13 (m, 2H), 3.07 (s, 3H), 3.65 (m, 2H), 3.79 (m, 2H),4.13 (m, 1H), 5.72 (m, 1H), 7.37 (m, 1H), 7.67 (m, 1H), 7.81 (m, 1H),7.87 (d, 2H), 7.97 (d, 2H), 8.41 (s, 1H), 8.60 (m, 2H), 10.19 (s, 1H).Exact mass calculated for C₂₂H₂₂N₆O₆S 498.13, found 499.3 (MH¹¹).

Example 9.27 Preparation of(4-Methanesulfonyl-phenyl)-[6-(1-methanesulfonyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]amine(Compound A27)

Compound A27 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (500,methanesulfonyl chloride (10 mg, 0.087 mmol), DMF (1 mL), ¹H NMR (CDCl₃,400 MHz) δ 2.13 (m, 4H), 2.85 (s, 3H), 3.08 (s, 3H), 3.31 (m, 2H), 3.57(m, 2H), 4.13 (m, 1H), 5.69 (m, 1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.42(s, 1H), 10.21 (s, 1H). Exact mass calculated for C₁₄H₂₁N₅O₇S₂ 471.09,found 472.3 (MH¹¹).

Example 9.28 Preparation of(4-Methanesulfonyl-phenyl)-{5-nitro-6-[1-(propane-1-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine(Compound A28)

Compound A28 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (200,propane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), ¹H NMR(CDCl₃, 400 MHz) δ 1.09 (t, 3H), 1.90 (m, 2H), 2.07 (m, 4H), 2.95 (m,2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.57 (m, 2H), 5.67 (m, 1H), 7.87 (d,2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact mass calculatedfor C₁₉H₂₅N₅O₇S₂ 499.12, found 500.3 (MH⁺).

Example 9.29 Preparation of{6-[1-(Butane-1-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine(Compound A29)

Compound A29 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl),butane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), ¹H NMR(CDCl₃, 400 MHz) δ 0.98 (t, 3H), 1.51 (m, 2H), 1.83 (m, 2H), 2.07 (m,4H), 2.97 (m, 2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.58 (m, 2H), 5.68 (m,1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact masscalculated for C₂₀H₂₇N₅O₇S₂ 513.14, found 514.4 (MH⁺).

Example 9.30 Preparation of(4-Methanesulfonyl-phenyl)-{5-nitro-6-[1-(thiophene-2-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine(Compound A30)

Compound A30 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl),thiophene-2-sulfonyl chloride (9 mg, 0.049 mmol), DMF (0.6 mL), ¹H NMR(CDCl₃, 400 MHz) δ 2.07 (m, 4H), 3.08 (s, 3H), 3.14 (m, 2H), 3.41 (m,2H), 5.53 (m, 1H), 7.31 (m, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.83 (m,2H), 7.95 (m, 2H), 8.37 (s, 1H), 10.14 (s, 1H). Exact mass calculatedfor C₂₀H₂₁N₅O₇S₃ 539.06, found 540.2 (MH⁺).

Example 9.31 Preparation of(4-Methanesulfonyl-phenyl)-{6-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-amine(Compound A31)

Compound A31 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μL),1-methyl-1H-imidazole-4-sulfonyl chloride (9 mg, 0.050 mmol), DMF (0.6mL), ¹H NMR (CDCl₃, 400 MHz) δ 2.07 (m, 4H), 3.08 (s, 3H), 3.32 (m, 2H),3.53 (m, 2H), 3.79 (s, 3H), 5.55 (m, 1H), 7.46 (s, 1H), 7.53 (s, 1H),7.85 (d, 2H), 7.97 (d, 2H), 8.38 (s, 1H), 10.16 (s, 1H). Exact masscalculated for C₂₀H₂₃N₇O₇S₂ 537.11, found 538.4 (MH⁺).

Example 9.32 Preparation of{6-[1-(2,4-Dimethyl-thiazole-5-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine(Compound A32)

Compound A32 was prepared in a similar manner as described above using(4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 pt),2,4-dimethyl-thiazole-5-sulfonyl chloride (10 mg, 0.047 mmol), DMF (0.6mL), ¹H NMR (CDCl₃, 400 MHz) δ 2.09 (m, 4H), 2.67 (s, 3H), 2.75 (s, 3H),3.08 (s, 3H), 3.21 (m, 2H), 3.50 (m, 2H), 5.58 (m, 1H), 7.85 (d, 2H),7.97 (d, 2H), 8.38 (s, 1H), 10.14 (s, 1H). Exact mass calculated forC₂₁H₂₄N₆O₇S₃ 568.09, found 569.4 (MH⁺).

Example 9.33 Preparation of4-[5-Cyano-6-(3-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A33)

Compound A33 was prepared in a similar manner as described in Example9.1 as a yellow solid (78%). ¹H NMR (CDCl₃, 400 MHz) δ 1.48 (s, 9H),1.80-1.86 (m, 2H), 1.90-1.98 (m, 2H), 3.23 (s, 3H), 3.34-3.40 (m, 2H),3.73-3.78 (m, 2H), 5.44-5.46 (m, 1H), 7.34-7.37 (m, 2H), 7.92-7.96 (m,1H), 8.04-8.07 (m, 1H), 8.55 (s, 1H). Exact mass calculated forC₂₂H₂₆FN₅O₅S 491.1, found 492.3 (MH⁺).

Example 9.34 Preparation of4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A34)

Compound A34 was prepared in a similar manner as described in Example9.1 as a yellow solid (287 mg, 93%). ¹H NMR 400 MHz CDCl₃₀ δ (ppm): 10.3(s, NH), 8.69 (t, 1H), 8.45 (s, 1H), 7.78 (t, 2H), 5.60 (m, 1H),3.64-3.61 (m, 2H), 3.56 (m, 2H), 3.09 (s, 3H), 1.97 (m, 2H), 1.88-1.84(m, 2H), 1.48 (s, 9H). Exact mass calculated for C₂₁H₂₆FN₅O₇S 511.15,LCMS (ESI) m/z 534.3 (M+H⁺+Na, 100%).

Example 9.35 Preparation of4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A35)

Compound A35 was prepared in a similar manner as described in Example9.1 as a white solid (1.930 g, 72%). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.51(s, 1H), 7.96 (d, 2H), 7.86 (d, 2H), 7.37 (s, NH), 5.44 (m, 1H),3.78-3.73 (m, 2H), 3.40-3.33 (m, 2H), 3.07 (s, 3H), 1.99 (m, 2H),1.85-1.82 (m, 2H), 1.48 (s, 9H). Exact mass calculated for C₂₂H₂₇N₅O₅S473.17, LCMS (ESI) m/z 474.1 (M+H⁺, 100%).

Example 9.36 Preparation of4-[6-(6-Methanesulfonyl-pyridin-3-ylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A36)

Compound A36 was prepared in a similar manner as described in Example9.1 as a yellow solid (1.848 g, 76%). ¹H NMR 400 MHz CDCl₃ δ (ppm): 10.2(s, NH), 8.92 (s, 1H), 8.43 (d, 1H), 8.42 (s, 1H), 8.13 (d, 1H), 5.61(m, 1H), 3.64-3.61 (m, 2H), 3.56-3.51 (m, 2H), 3.24 (s, 3H), 1.96 (m,2H), 1.91-1.88 (m, 2H), 1.48 (s, 9H), Exact mass calculated for C₂₀H₂₆N₆O₇S 494.16, LCMS (ESI) m/z 495.1 (M+H⁺, 100%).

Example 9.37 Preparation of4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A37)

4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.2 mmol, 633mg) and sodium hydride (3.2 mmol, 76 mg) were dissolved in N,N-dimethylacetamide (1.5 mL) and stirred for 30 minutes at room temperature.Subsequently, compound1-[4-chloro-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone(0.63 mmol, 207 mg) was added. The reaction was stirred at 70° C. for 30minutes. Progress of the reaction was monitored by thin layerchromatography and LCMS. Sodium hydride was carefully quenched withwater and the desired compound was extracted with ethyl acetate. Organicsolvents were evaporated in vacuo and purified by flash chromatography(Silica gel 60; 50/50 EtoAc/Hexanes) to afford Compound A37 as a yellowsolid (156 mg, 50%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 12.19 (s, 1H),8.95 (s, 1H), 8.56 (d, 1H), 8.44 (s, 1H), 8.07 (d, 1H), 5.56 (h, 1H),3.82 (m, 2H), 3.31 (m, 2H), 3.23 (s, 3H), 2.70 (s, 3H), 2.11 (m, 2H),1.85 (m, 2H), 1.48 (s, 9H). LCMS (ESI), m/z 492.4 (M+H⁺, 100%).

Example 9.38 Preparation of4-[5-Amino-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (Compound A38)

Compound A34 was subjected to hydrogenation conditions, H₂ in thepresence of 10% Pd/C and ethyl acetate to provide compound A38 as ayellow solid (503 mg, 89%). ¹H NMR 400 MHz CDCl₃ δ (ppm): 8.63 (t, 1H),8.18 (s, 1H), 7.72 (d, 1H), 7.69 (d, 1H), 7.16 (s, NH), 5.32 (m, 1H),3.82 (m, 2H), 3.30-3.24 (m, 2H), 3.05 (s, 3H), 2.03 (m, 2H), 1.76 (m,2H), 1.48 (s, 9H). Exact mass calculated for C₂₁H₂₈FN₅O₅S 481.18, LCMS(ESI) m/z 482.3 (M+⁺, 100%).

Example 9.39 Preparation of4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A39)

Compound A39 was obtained in a similar manner as described in Example9.10 as a solid (80%). ¹H NMR (CDCl₃, 400 MHz) δ 1.26 (d, 6H), 1.82-1.86(m, 2H), 1.90-1.99 (m, 2H), 3.07 (s, 3H), 3.39-3.45 (m, 2H), 3.76-3.82(m, 2H), 4.94 (sept, 1H), 5.44-5.48 (m, 1H), 7.37 (s, 1H), 7.85-7.87 (m,2H), 7.95-7.97 (m, 2H), 8.52 (s, 1H). Exact mass calculated forC₂₁H₂₅N₅O₅S 459.2, found 460.2 (MH⁺).

Example 9.40 Preparation of4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester (Compound A40)

Compound A40 was obtained in a similar manner as described in Example9.10 as a solid (75%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (t, 3H), 1.82-1.86(m, 2H), 1.90-1.99 (m, 2H), 3.07 (s, 3H), 3.39-3.45 (m, 2H), 3.76-3.82(m, 2H), 4.16 (q, 2H), 5.44-5.48 (m, 1H), 7.37 (s, 1H), 7.85-7.87 (m,2H), 7.95-7.97 (m, 2H), 8.52 (s, 1H). Exact mass calculated forC₂₀H₂₃N₅O₅S 445.1, found 446.2 (MH⁺).

Example 9.41 Preparation of4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester (Compound A41)

Compound A41 was obtained in a similar manner as described in Example9.10 as a solid (76%). ¹H NMR (CDCl₃, 400 MHz) δ 0.95 (d, 6H), 1.82-1.86(m, 2H), 1.90-1.99 (m, 2H), 3.07 (s, 3H), 3.42-3.48 (m, 2H), 3.76-3.82(m, 2H), 3.89 (d, 2H), 5.44-5.48 (m, 1H), 7.37 (s, 1H), 7.85-7.87 (m,2H), 7.95-7.97 (m, 2H), 8.52 (s, 1H). Exact mass calculated forC₂₂H₂₇N₅O₅S 473.2, found 474.3 (MH⁺).

Example 9.42 Preparation of4-(4-Methanesulfonyl-phenylamino)-6-[1-(tetrahydro-furan-2-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile(Compound A42)

Compound A42 was obtained in a similar manner as described in Example9.24 as a solid (75%). ¹H NMR (CDCl₃, 400 MHz) δ 1.87-2.06 (m, 8H),2.31-2.34 (m, 1H), 3.07 (s, 3H), 3.49-3.50 (m, 1H), 3.74-3.99 (m, 4H),4.64 (t, 1H), 5.54-5.56 (m, 1H), 7.40-7.42 (m, 1H), 7.85-7.88 (m, 2H),7.95-7.97 (m, 2H), 8.52 (s, 1H). Exact mass calculated for C₂₂H₂₅N₅O₅S471.2, found 472.2 (MH⁺).

Example 9.43 Preparation of4-[1-(3,3-Dimethyl-2-oxo-butyl)-piperidin-4-yloxy]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile(Compound A43)

Compound A43 was obtained in a similar manner as described in Example9.5 as a solid (70%). ¹H NMR (CDCl₃, 400 MHz) δ 1.17 (s, 9H), 1.95-1.99(m, 2H), 2.00-2.11 (m, 2H), 2.48-2.52 (m, 2H), 2.70-2.75 (m, 2H), 3.07(s, 3H), 3.48 (s, 2H), 5.44-5.48 (m, 1H), 7.37 (s, 1H), 7.85-7.87 (m,2H), 7.95-7.97 (m, 2H), 8.52 (s, 1H). Exact mass calculated forC₂₃H₂₉N₅O₄S 471.2, found 472.2 (MH⁺).

Example 9.44 Preparation of4-(4-Methanesulfonyl-phenylamino)-6-[1-(pyridine-3-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile(Compound A44)

Compound A44 was obtained in a similar manner as described in Example9.24 as a solid (88%). ¹H NMR (CDCl₃, 400 MHz) δ 1.80-2.14 (m, 4H), 3.07(s, 3H), 3.40-4.01 (m, 4H), 5.56-5.60 (m, 1H), 7.38-7.44 (m, 2H),7.79-7.81 (m, 1H), 7.85-7.87 (m, 2H), 7.95-7.97 (m, 2H), 8.52 (s, 1H),8.70 (s, 1H). Exact mass calculated for C₂₃H₂₂N₆O₄S 478.1, found 479.3(MH⁺).

Example 9.45 Preparation of4-(1-Formyl-piperidin-4-yloxy)-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile(Compound A45)

Compound A45 was obtained in a similar manner as described in Example9.24 as a solid (60%). ¹H NMR (CDCl₃, 400 MHz) δ 1.93-2.07 (m, 4H), 3.07(s, 3H), 3.42-3.48 (m, 1H), 3.66-3.76 (m, 3H), 5.56-5.60 (m, 1H), 7.36(s, 1H), 7.85-7.87 (m, 2H), 7.96-7.98 (m, 2H), 8.13 (s, 1H), 8.53 (s,1H). Exact mass calculated for C₁₈H₁₉N₅O₄S 401.1, found 402.4 (MH⁺).

Example 9.46 Preparation of4-(4-Methanesulfonyl-phenylamino)-6-[1-(pyridine-2-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile(Compound A46)

Compound A46 was obtained in a similar manner as described in Example9.24 as a solid (23%). ¹H NMR (CDCl₃, 400 MHz) δ 1.90-2.14 (m, 4H), 3.07(s, 3H), 3.46-3.48 (m, 1H), 3.69-3.97 (m, 3H), 5.56-5.60 (m, 1H), 7.47(s, 1H), 7.54-7.58 (m, 1H), 7.70-7.72 (m, 1H), 7.85-7.87 (m, 2H),7.95-7.97 (m, 2H), 8.01-8.03 (m, 1H), 8.52 (s, 1H), 8.73-8.74 (m, 1H).Exact mass calculated for C₂₃H₂₂N₆O₄S 478.1, found 479.2 (MH⁺).

Example 9.47 Preparation of4-[5-Cyano-6-(2-fluoro-4-isopropylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A63)

4-[5-Cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (250 mg, 0.48 mmol), isopropylamine (408 μL, 4.8mmol), proline (99 mg, 0.86 mmol), copper iodide (92 mg, 0.48 mmol) andpotassium carbonate (152 mg, 1.1 mmol) were mixed together in DMSO (4mL). The reaction vessel was heated in a microwave at 80° C. for 1.0hour. Progress of the reaction was monitored by TLC and LCMS.Purification by HPLC afforded compound A63 as a white solid (50 mg,23%). ¹H NMR (CDCl₃, 400 MHz) δ 8.37 (s, 1H), 7.99 (t, 1H), 7.12 (s,1H), 6.93 (t, 2H), 5.38 (h, 1H), 4.87 (h, 1H), 3.72 (m, 2H), 3.52 (m,1H), 1.91 (m, 2H), 1.77 (m, 2H), 1.92 (m, 2H), 1.26 (d, 6H), 1.13 (d,6H). Exact mass calculated for C₂₃H₂₉FN₆O₃ 456.51, found 457.1 (MH⁺).

Example 9.48 Preparation of4-[5-Cyano-6-(2-fluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A64)

4-[5-Cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (250 mg, 0.48 mmol), n-propylamine (408 μL, 4.8mmol), proline (99 mg, 0.86 mmol), copper iodide (92 mg, 0.48 mmol) andpotassium carbonate (152 mg, 1.1 mmol) were mixed together in DMSO (4mL). The reaction vessel was heated in a microwave at 80° C. for 30minutes. Progress of the reaction was monitored by TLC and LCMS.Purification by HPLC afforded compound A64 as a white solid (80 mg,37%). ¹H NMR (CDCl₃, 400 MHz) δ 9.37 (s, 1H), 8.22 (s, 1H), 6.91 (t,1H), 6.91 (m, 2H), 5.27 (h, 1H), 4.71 (h, 1H), 3.53 (m, 2H), 3.23 (m,2H), 2.91 (m, 2H), 1.85 (m, 2H), 1.54 (m, 4H), 1.13 (d, 6H), 0.88 (t,3H). Exact mass calculated for C₂₃H₂₉FN₆O₃ 456.51, found 457.4 (MH⁺).

Example 9.49 Preparation of4-[5-Cyano-6-(2-fluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A65)

A mixture of4-[5-cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (250 mg, 0.48 mmol), propan-1-ol (2 mL, excess),copper iodide (9.1 mg, 0.048 mmol), 1,10-phenanthroline (18.1 mg, 0.096mmol) and cesium carbonate (313 mg, 0.96 mmol) in dioxane (3.5 mL) washeated under microwave irradiation for 30 min at 90° C. The crudemixture was concentrated in vacuo and purified by HPLC to providecompound A65 as a white solid (10 mg, 12%). Exact mass calculated forC₂₃H₂₈FN₅O₄ 457.50, found 458.8 (MH⁺).

Example 9.50 Preparation of4-[5-Cyano-6-(6-propyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A66)

In a 25 mL round-bottomed flask fitted with a condenser and N₂ inlet wasplaced4-[6-(6-chloro-pyridin-3-ylamino)-5-cyano-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (100 mg, 1.3 mmol), n-propylzinc bromide (0.5M inTHF, 0.72 mL), tetrakis (triphenylphosphino)palladium (28 mg, 0.024mmol), and THF (3.5 mL). The reaction mixture was refluxed overnightunder N₂ atmosphere. The product was purified by preparative HPLC. ¹HNMR (CDCl₃, 400 MHz) δ 1.03 (t, 3H), 1.26 (d, 6H), 1.85 (m, 4H), 1.98(m, 2H), 3.04 (t, 2H), 3.44 (m, 2H), 3.77 (m, 2H), 4.94 (m, 1H), 5.46(m, 1H), 7.57 (d, 1H), 8.34 (s, 1H), 8.51 (s, 1H), 8.56 (d, 1H), 9.42(s, 1H). Exact mass calculated for C₂₂H₂₈N₆O₃ 424.22, found 425.2 (MH⁺).

Example 9.51 Preparation of4-{5-Cyano-6-[4-(2-dimethylamino-ethylsulfanyl)-2-fluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A67)

In a microwave reaction tube was placed4-[5-cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (10 mg, 0.19 mmol), 2-dimethylamino-ethanethiol (27mg, 0.19 mmol), di-m-bromobis (tri-t-butylphosphino)dipalladium (I) (8mg, 0.0095 mmol), sodium t-butoxide (55 mg, 0.57 mmol), and DMSO (0.5mL). The reaction mixture was heated at 120° C. under microwave for 4hours. The resulting mixture was filtered through a syringe filter andpurified by preparative HPLC. ¹H NMR (CDCl₃, 400 MHz) δ 1.26 (d, 6H),1.86 (m, 2H), 2.00 (m, 2H), 2.86 (s, 6H), 3.20 (m, 2H), 3.30 (m, 2H),3.43 (m, 2H), 3.78 (m, 2H), 4.94 (m, 1H), 5.44 (m, 1H), 7.22 (s, 1H),7.24 (s, 1H), 7.35 (s, 1H), 8.11 (t, 1H), 8.45 (s, 1H). Exact masscalculated for C₂₄H₃₁ FN₆O₃S 502.22, found 503.2 (MH⁺).

Example 9.52 Preparation of4-{5-Cyano-6-[4-(2-dimethylamino-ethanesulfonyl)-2-fluoro-phenylamino]-3-oxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A68)

In a 50 mL round-bottomed flask immersed in an ice-bath was place a stirbar,4-{5-cyano-6-[4-(2-dimethylamino-ethylsulfanyl)-2-fluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (25 mg, 0.04 mmol) and CH₂Cl₂ (15 mL). mCPBA (20mg, 0.089 mmol) dissolved in CH₂Cl₂ (2 mL) was added dropwise at 0° C.The resulting mixture was stirred at 0° C. for 1 h and subsequentlyquenched with sodium bisulfite solution. The organic layer wasseparated. The aqueous layer was extracted with CH₂Cl₂. The combinedorganic extracts was dried and concentrated under vacuum to give thecrude product. The crude was purified by preparative HPLC. Exact masscalculated for C₂₄H₃₁FN₆O₆S 550.20, found 551.2 (MH⁺).

Example 9.53 Preparation of4-[5-Cyano-6-(2-fluoro-4-morpholin-4-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A71)

A mixture of4-[5-cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (60 mg, 0.114 mmol), morpholine (50 μL, 0.571mmol), CuI (21 mg, 0.114 mmol), proline (23 mg, 0.205 mmol) andpotassium carbonate (36 mg, 0.262 mmol) in DMSO (1 mL) was heated inmicrowave for 30 minutes at 80° C. The mixture was purified by HPLC togive Compound A71 as a solid (25.1 mg, 45%). ¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.31 (s, 1H), 7.61 (t, 1H), 7.08 (s, 1H), 6.69 (m, 2H), 5.35 (m,1H), 4.86 (m, 1H), 3.82 (m, 4H), 3.68 (m, 2H), 3.38 (m, 2H), 3.19 (m,4H), 1.90 (m, 2H), 1.75 (m, 2H), 1.18 (d, 6H). Exact mass calculated forC₂₄H₂₉FN₆O₄ 484.22, found 485.2 (MH⁺).

Example 9.54 Preparation of4-[5-Cyano-6-(4-dimethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A73)

Compound A73 was prepared in a similar procedure as described in Example9.53 as a brownish solid (20 mg, 39.6%). ¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.41 (s, 1H), 7.97 (t, 1H), 7.37 (s, 1H), 6.99 (m, 2H), 5.42 (m,1H), 4.92 (m, 1H), 3.73 (m, 2H), 3.44 (m, 2H), 3.09 (s, 6H), 1.95 (m,2H), 1.85 (m, 2H), 1.23 (d, 6H). Exact mass calculated for C₂₂H₂₇FN₆O₃442.49, found 443.3 (MH⁺).

Example 9.55 Preparation of4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A75)

Compound A75 was obtains as a tan solid (HCl salt, 219 mg, 21%). ¹H NMR(MeOH-d₄, 400 MHz) δ 1.17-1.18 (d, 6H), 1.66-1.78 (m, 2H), 1.87-2.01 (m,2H), 2.12 (s, 3H), 3.10 (s, 3H), 3.18-3.234 (m, 1H), 3.36 (m, 2H),3.53-3.73 (m, 2H), 5.28-5.39 (m, 1H), 7.73-7.88 (m, 3H), 8.25 (s, 1H).Exact mass calculated for C₂₁H₂₇FN₄O₅S 466.17, found 467.5 (MH⁺).

Example 9.56 Preparation of4-[6-(2-Fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A77) Step 1: Preparation of the4-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester

To a solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester(6.26 g, 33.4 mmol) and 4,6-dichloro-5-methyl-pyrimidine (5.45 g, 33.4mmol) in 100 mL THF, 1M potassium tert-butoxide in THF (40 mL, 40 mmol)were added slowly by syringe pump. After 1 hour, everything had beenadded and mixture was concentrated. Residue was extracted with methylenechloride and water. Organic phases were dried over magnesium sulfate,filtered, and concentrated to give4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester as a pale yellow solid (10.3 g, 98%). ¹H NMR (CDCl₃, 400MHz) δ 1.22-1.24 (d, 6H), 1.74-1.81 (m, 2H), 1.95-2.04 (m, 2H), 2.24 (s,3H), 3.40-3.45 (m, 2H), 3.74-3.81 (m, 2H), 4.90-4.98 (m, 1H), 5.31-5.37(m, 1H), 8.40 (s, 1H).

Step 2: Preparation of4-[6-(2-Fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A77)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (2.58 g, 8.22 mmol), palladium acetate (185 mg, 0.82mmol), biphenyl-3-yl-di-tert-butyl-phosphane (25 mg, 0.08 mmol), sodiumtert-butoxide (2.4 g, 21.2 mmol), and 4-iodo-2-fluoro aniline (2.0 g,8.4 mmol) in 15 mL dioxane was heated in microwave for 1 hour at 120° C.Solids were filtered off and mixture was purified by columnchromatography and precipitating out of hexane/AcOEt to give compoundA77 as a tanned solid (1.99 g, 47%). ¹H NMR (CDCl₃, 400 MHz) δ 1.15-1.16(d, 6H), 1.61-1.71 (m, 2H), 1.85-1.90 (m, 2H), 1.99 (s, 3H), 3.27-3.33(m, 2H), 3.63-3.66 (m, 2H), 4.82-4.85 (m, 1H), 5.20-5.23 (m, 1H),6.35-6.36 (d, 1H), 7.33-7.36 (m, 2H), 8.08-8.13 (m, 1H), 8.22 (s, 1H).Exact mass calculated for C₂₀H₂₄F₁N₄O₃ 514.09, found 515.2 (MH⁺).

Example 9.57 Preparation of4-[6-(2-Fluoro-4-morpholin-4-yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A79)

Compound A79 was obtained in a similar manner as described in Example9.47 as a white solid (HCl salt, 401 mg, 38%). ¹H NMR (MeOH-d₄, 400 MHz)δ 1.03-1.05 (d, 6H), 1.53-1.68 (m, 3H), 1.79-1.88 (m, 2H), 1.98 (s, 3H),3.05-3.09 (m, 3H), 3.15-3.25 (m, 2H), 3.49-3.57 (m, 3H), 3.62-3.65 (m,4H), 4.69-4.63 (m, 1H), 5.24-5.28 (m, 1H), 6.74-6.80 (m, 1H), 7.08-7.12(m, 1H), 8.06 (s, 1H). Exact mass calculated for C₂₅H₃₂FN₅O₄ 473.24,found 474.7 (MH⁺).

Example 9.58 Preparation of4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A80)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (330 mg, 1.05 mmol), palladium acetate (23.6 mg, 0.01mmol), biphenyl-3-yl-di-tert-butyl-phosphane (4 mg, 0.013 mmol), sodiumtert-butoxide (330 mg, 3.43 mmol), and2,5-difluoro-4-propoxy-phenylamine (HCl salt, 235 mg, 1.05 mmol) in 15mL dioxane was heated in microwave for 1 hour at 120° C. Mixture waspurified by HPLC and treated with THF to give compound A80 as a whitesolid (HCl salt, 140 mg, 27%). ¹H NMR (CDCl₃, 400 MHz) δ 0.88-0.92 (t,3H), 1.08-1.09 (d, 6H), 1.62-1.73 (m, 4H), 1.83-1.91 (m, 2H), 2.02 (s,3H), 3.22-3.30 (m, 2H), 3.53-3.60 (m, 2H), 3.88-3.91 (t, 2H), 4.70-4.74(m, 1H), 5.29-5.30 (m, 1H), 6.99-7.04 (m, 1H), 7.10-7.15 (m, 1H), 8.12(s, 1H). Exact mass calculated for C₂₃H₃₀F₂N₄O₄ 464.22, found 465.4(MH⁺).

Example 9.59 Preparation of4-[6-(2-Fluoro-4-propylamino-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A81)

A mixture of4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (100 mg, 196 mmol), L-proline (45 mg, 0.39 mmol),copper iodide (37.6 mg, 0.198 mmol), and propylamine (321 μl, 3.91 mmol)in 4 mL DMSO was heated in microwave for 1 hour at 80° C. Mixture waspurified by HPLC to give Compound A81 as a white solid (TFA salt, 108.6mg, 99%). ¹H NMR (MeOH-d₄, 400 MHz) δ 0.80-0.84 (t, 3H), 1.06-1.07 (d,6H), 1.44-1.50 (m, 2H), 1.57-1.62 (m, 2H), 1.79-1.97 (m, 2H), 1.97 (s,3H), 2.90-2.93 (m, 2H), 3.20-3.29 (m, 2H), 3.54-3.58 (m, 2H), 4.68-4.72(m, 1H), 5.23-5.26 (m, 1H), 6.37-6.41 (m, 1H), 6.96-7.00 (m, 1H), 8.01(s, 1H). Exact mass calculated for C₂₂H₃₂FN₅O₃ 445.25, found 446.3(MH⁺).

Example 9.60 Preparation of4-{6-[2-Fluoro-4-(2-methoxy-ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A82)

A mixture of4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (100 mg, 196 mmol), 1-proline (45 mg, 0.39 mmol),copper iodide (37.6 mg, 0.198 mmol), and 2-methoxyethylamine (340 μl,3.91 mmol) in 4 mL DMSO was heated in microwave for 1 hour at 80° C.Mixture was purified by HPLC to give Compound A82 as a white solid (TFAsalt, 101.7 mg, 90%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.21-1.22 (d, 6H),1.71-1.78 (m, 2H), 1.96-2.01 (m, 2H), 2.13 (s, 3H), 3.34 (s, 3H),3.34-3.45 (m, 2H), 3.53-3.56 (t, 2H), 3.70-3.73 (m, 2H), 4.81-4.87 (m,1H), 5.38-5.42 (m, 1H), 6.64-6.57 (m, 1H), 7.09-7.13 (m, 1H), 8.17 (s,1H). Exact mass calculated for C₂₂H₃₂FN₅O₃ 461.24, found 462.4 (MH1).

Example 9.61 Preparation of4-(6-{2-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound A83)

A mixture of4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (100 mg, 196 mmol), L-proline (45 mg, 0.39 mmol),copper iodide (37.6 mg, 0.198 mmol), andC-(tetrahydro-furan-2-yl)-methylamine (404 μl, 3.91 mmol) in 4 mL DMSOwas heated in microwave for 1 hour at 80° C. Mixture was purified byHPLC to give Compound A83 as a white solid (TFA salt, 119 mg, 100%). ¹HNMR (MeOH-d₄, 400 MHz) δ 1.51-1.53 (d, 6H), 1.90-2.10 (m, 3H), 2.12-2.38(m, 5H), 2.43 (s, 3H), 3.40-3.49 (m, 2H), 3.75-3.83 (m, 2H), 3.98-4.06(m, 3H), 4.10-4.19 (m, 1H), 4.30-4.38 (m, 1H), 5.13-5.17 (m, 1H),5.69-5.72 (m, 1H), 6.85-6.87 (m, 2H), 7.37-7.41 (m, 1H), 8.47 (s, 1H).Exact mass calculated for C₂₂H₃₂FN₅O₃ 487.26, found 488.3 (MH¹).

Example 9.62 Preparation of4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A84)

A mixture of4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (100 mg, 196 mmol), 1-proline (45 mg, 0.39 mmol),copper iodide (37.6 mg, 0.198 mmol), and 2-methanesulfonyl-ethylamine(307 μl, 2.5 mmol) in 4 mL DMSO was heated in microwave for 1 hour at80° C. Mixture was purified by HPLC to give Compound A84 as a whitesolid (TFA salt, 52.9 mg, 44%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.17-1.18(d, 6H), 1.68-1.72 (m, 2H), 1.91-1.95 (m, 2H), 2.08 (s, 3H), 2.93 (s,3H), 3.28-3.37 (m, 4H), 3.58-3.67 (m, 4H), 4.78-4.82 (m, 1H), 5.32-5.36(m, 1H), 6.48-6.53 (s, 2H), 7.06-7.10 (m, 1H), 8.11 (s, 1H). Exact masscalculated for C₂₃H₃₂FN₅O₅S 509.21, found 510.5 (MH¹).

Example 9.63 Preparation of4-(6-{2-Fluoro-4-[(2-methanesulfonyl-ethyl)-methyl-amino]-phenylamino}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound A85)

A mixture of4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (100 mg, 196 mmol), L-proline (45 mg, 0.39 mmol),copper iodide (37.6 mg, 0.198 mmol), and(2-Methanesulfonyl-ethyl)-methyl-amine (268 μl, 1.95 mmol) in 4 mL DMSOwas heated in microwave for 3 hours at 80° C. and for 2 hours at 90° C.Mixture was purified by HPLC to give Compound A85 as a white solid (TFAsalt, 22.4 mg, 18%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.04-1.06 (d, 6H),1.51-1.62 (m, 2H), 1.78-1.89 (m, 2H), 1.95 (s, 3H), 2.79 (s, 3H), 2.82(s, 3H), 3.19-3.23 (m, 4 H), 3.50-3.60 (m, 2H), 3.68-3.72 (t, 2H),4.66-4.70 (m, 1H), 5.19-5.22 (m, 1H), 6.50-6.53 (m, 2H), 7.01-7.06 (m,1H), 7.96 (s, 1H). Exact mass calculated for C₂₄H₃₄FN₅O₅S 523.23, found524.4 (MH⁺).

Example 9.64 Preparation of4-[6-(4-Bromo-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A86)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.03 g, 3.28 mmol), palladium acetate (74 mg, 0.33mmol), biphenyl-3-yl-di-tert-butyl-phosphane (9.7 mg, 0.033 mmol),sodium tert-butoxide (708 mg, 7.36 mmol), and4-bromo-2,5-difluoro-phenylamine (706 mg, 3.39 mmol) in 15 mL dioxanewas heated in microwave for 1 hour at 120° C. Solids were filtered offand mixture was purified by column chromatography (hexane/AcOEt) andcrystallized from hexane/AcOEt to give compound A86 as a tanned solid(652 mg, 41%). ¹H NMR (CDCl₃, 400 MHz) δ 1.04-1.05 (d, 6H), 1.50-1.61(m, 2H), 1.74-1.82 (m, 2H), 1.89 (s, 3H), 3.16-3.22 (m, 2H), 3.51-3.60(m, 2H), 4.69-4.76 (m, 1H), 5.09-5.15 (m, 1H), 6.34-6.36 (m, 1H),7.07-7.11 (m, 1H), 8.15 (s, 1H), 8.34-8.38 (m, 1H). Exact masscalculated for C₂₀H₂₃BrF₂N₄O₃ 484.09, found 485.2 (MH⁺).

Example 9.65 Preparation of4-[6-(4-Cyano-2-fluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A87)

Compound A87 was obtains as a tanned solid (TFA salt, 387.1 mg, 28%). ¹HNMR (MeOH-d₄, 400 MHz) δ 1.118-1.221 (d, J=6.32 Hz, 6H), 1.608-1.724 (m,2H), 1.859-1.966 (m, 2H), 2.064 (s, 3H), 3.289-3.404 (m, 2H),3.607-3.727 (m, 2H), 4.73-4.82 (m, 1H), 5.220-5.310 (m, 1H), 7.409 (d,1H), 7.545 (d, 1H), 7.954-8.031 (t, J=8.08 Hz, 1H), 8.145 (s, 1H). Exactmass calculated for C₂₁H₂₄FN₅O₃ 413.19, found 414.4 (MH⁺).

Example 9.66 Preparation of4-[6-(4-Cyano-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A88)

Compound A88 was obtains as a white solid (TFA salt, 309.8 mg, 22%). ¹HNMR (DMSO-d₆, 400 MHz) δ 1.18-1.20 (d, J=6.32 Hz, 6H), 1.57-1.66 (m,2H), 1.89-1.94 (m, 2H), 2.1 (s, 3H), 3.30-3.35 (m, 2H), 3.59-3.65 (m,1H), 4.73-4.82 (m, J=6.32 Hz, 2H), 5.24-5.30 (m, J=3.79 Hz, 1H),7.88-7.93 (dd, J=11.37, 6.57 Hz, 1H), 7.93-7.98 (dd, J=10.36, 6.06 Hz,1H), 8.31 (s, 1H), 8.72 (s, 1H). Exact mass calculated for C₂₁H₂₃F₂N₅O₃431.18, found 432.3 (MH⁺).

Example 9.67 Preparation of4-[6-(2,5-Difluoro-4-morpholin-4-yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A89)

A mixture of4-[6-(4-bromo-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (645 mg, 1.33 mmol), L-proline (306 mg, 2.66 mmol),copper iodide (253 mg, 1.33 mmol), potassium carbonate (211 mg, 1.53mmol), and morpholine (2.3 mL, 26 mmol) in 15 mL DMSO was heated inmicrowave for 18 hours at 80° C. Mixture was purified by HPLC to giveCompound A89 as a tanned solid (HCl salt, 251 mg, 30%). ¹H NMR (MeOH-d₄,400 MHz) δ 1.05-1.07 (d, 6H), 1.52-1.63 (m, 2H), 1.80-1.89 (m, 2H), 1.99(s, 3H), 2.94-2.96 (m, 4H), 3.21-3.29 (m, 2H), 3.54-3.70 (m, 6H),5.22-5.29 (m, 1H), 6.82-6.86 (m, 1H), 7.03-7.08 (m, 1H), 8.10 (s, 1H).Exact mass calculated for C₂₄H₃₁F₂N₅O₄ 491.23, found 492.5 (MH⁺).

Example 9.68 Preparation of4-[6-(6-Chloro-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A90)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.546 g, 4.93 mmol), palladium acetate (110 mg, 0.49mmol), biphenyl-3-yl-di-tert-butyl-phosphane (18.5 mg, 0.062 mmol),sodium tert-butoxide (1.20 g, 12.5 mmol), and6-chloro-2-methyl-pyridin-3-ylamine (709 mg, 4.97 mmol) in 15 mL dioxanewas heated in microwave for 2 hour at 120° C. Solids were filtered offand mixture was purified to give Compound A90 as a tanned solid (640 mg,31%). ¹H NMR (CDCl₃, 400 MHz) δ 1.11-1.12 (d, 6H), 1.52-1.62 (m, 2H),1.81-1.89 (m, 2H), 1.98 (s, 3H), 2.23 (m, 3H), 3.21-3.30 (m, 2H),3.59-3.70 (m, 3H), 5.14-5.17 (m, 1H), 6.83-6.91 (m, 1H), 7.14-7.16 (d,1H), 7.55-7.57 (d, 1H), 7.87 (s, 1H). Exact mass calculated forC₂₀H₂₆ClN₅O₃ 419.17, found 419.9 (MH⁺).

Example 9.69 Preparation of4-[5-(4,5-Dihydro-1H-imidazol-2-yl)-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A92)

To a solution of zinc chloride (28 mg, 0.149 mmol) and4-[5-cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (1 g, 2.09 mmol) in chlorobenzene (15 mL),ethane-1,2-diamine (0.100 mL, 1.463 mmol) was added. The mixture washeated under reflux for 24 h. LCMS indicated desired product. The crudewas concentrated under vacuo and purified by HPLC to afford compound A92as a yellow solid (303 mg, 23%). ¹H NMR (CDCl₃, 400 MHz) δ 1.23 (d, 6H),1.68-1.77 (m, 2H), 2.05-2.09 (m, 2H), 3.07 (s, 3H), 3.16-3.23 (m, 2H),3.84-3.92 (m, 2H), 4.07 (s, 4H), 4.87-4.92 (m, 1H), 5.42-5.47 (m, 1H),7.50-7.62 (m, 2H), 7.79-7.83 (m, 1H), 8.35 (s, 1H). Exact masscalculated for C₂₃H₂₉FN₆O₅S 520.19, found 521.5 (MH⁺).

Example 9.70 Preparation of(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidin-4-yl}-amine(Compound A93)

A mixture of(6-chloro-5-methyl-pyrimidin-4-yl)-(2-fluoro-4-methanesulfonyl-phenyl)-amine(HCl salt, 1.76 g, 5.0 mmol) and1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (1.05 g, 5.0 mmol)in anhydrous THF (10 mL) was treated with potassium t-butoxide (20 mL,20 mmol), placed under inert atmosphere, and refluxed for 4 hours, atwhich point the reaction had stalled at 60% conversion. The reactionmixture was cooled, quenched with water (30 mL), and extracted withether (2×50 mL). The combined organic extract was rinsed with water (20mL), followed by brine (20 mL), and was dried over MgSO₄. After solventremoval, the residue was rinsed with boiling ether (2×20 mL), and thecombined rinses were set aside to cool. Crystallization yielded a whitesolid (91% pure by LCMS) which was triturated in hot ether and filteredhot to furnish Compound A93 as a white solid in >95% purity (731 mg, 30%yield). This material was taken up in CH₂Cl₂ (10 mL), to which was added1 N HCl/ether (1.5 mL). Upon solvent removal, a light gray foam wasobtained (800 mg): ¹H NMR (DMSO-d₆) δ 10.26 (brs, 1 H), 8.77 (s, 1 H),8.22 (s, 1 H), 7.83-7.71 (m, 3 H), 5.33 (m, 1 H), 3.75 (m, 2 H), 3.57(m, 2 H), 3.37 (s, 3 H), 2.83 (m 1 H), 2.13 (s, 3 H), 2.04 (m, 2 H),1.78 (m, 2 H), 1.20 (d, 6 H, J=6.9 Hz), MS m/z 491.2 (M⁺).

Example 9.71 Preparation of4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A95)

General procedure of coupling alcohol to aryl halides: A mixture of4-[6-(2-fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (103 mg, 0.2 mmole), cesium carbonate (130 mg, 0.4mmole), copper iodide (8 mg, 0.04 mmole), and 1,10-phenanthroline (14mg, 0.08 mmole) in 2-methanesulfonyl-ethanol (3 mL) was heated undermicrowave irradiation at 150° C. for 1 hour. The crude mixture waspurified by HPLC to provide

Compound A95 as a yellow solid (3 mg, 3%). Exact mass calculated forC₂₃H₃₁FN₄O₆S 510.2, found 511.3 (MH⁺).

Example 9.72 Preparation of4-[6-(2-Fluoro-4-propoxy-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A94)

Compound A94 was obtained in a similar manner as described in Example9.71 as a solid (38 mg, 84%). ¹H NMR (CDCl₃, 400 MHz) δ 1.04 (t, 3H),1.26 (d, 6H), 1.75-1.84 (m, 7H), 1.97-2.02 (m, 2H), 3.35-3.41 (m, 2H),3.74-3.77 (m, 2H), 3.91 (t, 2H), 4.93 (sept, 1H), 5.37-5.40 (m, 1H),6.67-6.72 (m, 2H), 7.27-7.30 (m, 1H), 8.32 (s, 1H), 9.30 (s, 1H). Exactmass calculated for C₂₃H₃₁FN₄O₄446.2, found 447.3 (MH⁺).

Example 9.73 Preparation of4-{6-[2-Fluoro-4-(2-methoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A96)

Compound A96 was obtained in a similar manner as described in Example9.71 as a tan solid (76 mg, 83%). ¹H NMR (CDCl₃, 400 MHz) δ 1.25 (d,J=6.3 Hz, 6H), 1.74-1.79 (m, 2H), 1.81 (s, 3H), 1.97-2.05 (m, 2H),3.35-3.41 (m, 2H), 3.45 (s, 3H), 3.75-3.77 (m, 4H), 4.10-4.12 (m, 2H),4.93 (sep, J=6.3 Hz, 1H), 5.36-5.41 (m, 1H), 6.72-6.75 (m, 2H), 7.36 (t,J=9.1 Hz, 1H), 8.31 (s, 1H), 9.15 (s, NH). Exact mass calculated forC₂₃H₃₁FN₄O₅ 462.2, found 463.5 (MH⁺).

Example 9.74 Preparation of4-{6-[2-Fluoro-4-(2-isopropoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A97)

Compound A97 was obtained in a similar manner as described in Example9.71 as a yellow solid (86 mg, 88%). ¹H NMR (CDCl₃, 400 MHz) δ 1.21 (d,J=6.1 Hz, 6H), 1.25 (d, J=6.3 Hz, 6H), 1.75-1.79 (m, 2H), 1.80 (s, 3H),1.97-2.02 (m, 2H), 3.35-3.42 (m, 2H), 3.70 (sep, J=6.3 Hz, 1H), 3.76(dd, J=4.0 Hz, 4.8 Hz, 4H), 4.09 (t, J=4.8 Hz, 2H), 4.93 (sep, J=6.3 Hz,1H), 5.37-5.41 (m, 1H), 6.73 (dd, J=11.6 Hz, 2H), 7.26 (t, J=8.6 Hz,1H), 8.32 (s, 1H), 9.36 (s, NH). Exact mass calculated for C₂₅H₃₅PN₄O₅490.3, found 491.4 (MH⁺).

Example 9.75 Preparation of4-[6-(6-Chloro-4-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A98)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.80 g, 5.74 mmol), palladium acetate (155 mg, 0.69mmol), biphenyl-3-yl-di-tert-butyl-phosphane (21.5 mg, 0.072 mmol),sodium tert-butoxide (1.38 g, 14.4 mmol), and6-chloro-4-methyl-pyridin-3-ylamine (838 mg, 5.80 mmol) in 20 mL dioxanewas heated in microwave for 1 hour at 120° C. Solids were filtered offand mixture was purified by column chromatography (hexane/AcOEt) to giveCompound A98 as a tanned solid (702 mg, 29%). ¹H NMR (CDCl₃, 400 MHz) δ1.24-1.26 (d, 6H), 1.72-1.81 (m, 2H), 1.95-2.02 (m, 2H), 2.10 (s, 3H),2.27 (s, 3H), 3.37-3.43 (m, 2H), 3.74-3.77 (m, 2H), 4.90-4.97 (m, 1H),5.29-5.34 (m, 1H), 5.91 (s, 1H), 7.00 (s, 1H), 8.22 (s, 1H), 8.57 (s,1H). Exact mass calculated for C₂₀H₂₆ClN₅O₃ 419.17, found 420.4 (MH⁺).

Example 9.76 Preparation of4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-(N-hydroxycarbamimidoyl)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A99)

4-[5-Cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (0.5 g, 1.04 mmol) was dissolved in the mixtureethanol/water (30 mL/14 mL) and heated to 80° C. Hydroxylaminehydrochloride (7.22 g, 104 mmol) and potassium carbonate (14.5 g, 105mmol) were slowly added and the mixture kept stirring at 80° C. for 1 h.The crude was filtered and the retrieved solid was thoroughly washedwith acetonitrile. The filtrate was concentrated under reduced pressure,yielding a yellow solid residue, which was purified by HPLC to affordCompound A99 (0.51 g, 78%). Exact mass calculated for C₂₁H₂₇FN₆O₆S510.17, found 511.2 (MH⁺).

Example 9.77 Preparation of4-[5-Carbamimidoyl-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A100)

4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-(N-hydroxycarbamimidoyl)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (0.510 g, 0816 mmol) was dissolved in acetic acidglacial (20 mL) and zinc dust (1 g, 16.32 mmol) was added. The reactionmixture was heated at 70° C. for 40 min. The crude was filtered, thefiltrate was concentrated under reduced pressure and the residue waspurified by HPLC to afford Compound A100 (43 mg, 8.65%). Exact masscalculated for C₂₁H₂₇FN₆O₅S 494.17, found 495.5 (MH⁺).

Example 9.78 Preparation of4-{6-[2-Fluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A101)

Compound A101 was obtained in a similar manner as described in Example9.71 as a solid (35 mg, 24%). ¹H NMR (CDCl₃, 400 MHz) δ 1.15 (d, 6H),1.66-1.73 (m, 5H), 1.87-2.02 (m, 6H), 3.27-3.34 (m, 2H), 3.66-3.89 (m,6H), 4.19-4.21 (m, 1H), 4.85 (sept, 1H), 5.28-5.30 (m, 1H), 6.64-6.67(m, 2H), 7.32 (t, 1H), 8.22 (s, 1H), 8.90 (s, 1H). Exact mass calculatedfor C₂₅H₃₃FN₄O₅ 488.2, found 489.5 (MH⁺).

Example 9.79 Preparation of4-{6-[6-(2-Methoxy-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A103)

A mixture of4-[6-(6-chloro-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (507 mg, 1.21 mmol) and potassium carbonate (1.62g, 12 mmol) in 4.5 mL 2-methoxyethanol was heated in microwave for 16.5hours at 180° C. Mixture was purified by HPLC to give Compound A103 as atanned solid (HCl salt, 103.5 mg, 17%). ¹H NMR (MeOH-d₄, 400 MHz) δ1.15-1.17 (d, 6H), 1.68-1.74 (m, 2H), 1.92-1.96 (m, 2H), 2.12 (s, 3H),2.44 (s, 3H), 3.28-3.37 (m, 5H), 3.64-3.70 (m, 4H), 4.43-4.46 (m, 2H),4.74-4.79 (m, 1H), 5.35-5.39 (m, 1H), 6.92-6.94 (d, 1H), 7.70-7.73 (d,1H), 8.16 (s, 1H). Exact mass calculated for C₂₃H₃₃N₅O₅ 459.25, found460.5 (MH⁺).

Example 9.80 Preparation of4-{6-[6-(2-Methoxy-ethoxy)-4-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A104)

A mixture of4-[6-(6-chloro-4-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (353 mg, 0.84 mmol) and potassium carbonate (1.1 g,7.96 mmol) in 4 mL 2-methoxyethanol was heated in microwave for 17 hoursat 180° C. Mixture was purified by HPLC to give Compound A104 as atanned solid (HCl salt, 61.8 mg, 15%). ¹H NMR (MeOH-d₄, 400 MHz) δ1.07-1.08 (d, 6H), 1.60-1.65 (m, 2H), 1.83-1.87 (m, 2H), 2.05 (s, 3H),2.15 (s, 3H), 3.21-3.32 (m, 5H), 3.54-3.61 (m, 4H), 4.34-4.36 (m, 2H),4.67-4.73 (m, 1H), 5.27-5.31 (m, 1H), 6.98 (s, 1H), 8.04 (s, 1H), 8.09(s, 1H). Exact mass calculated for C₂₃H₃₃N₅O₅ 459.25, found 460.3 (MH⁺).

Example 9.81 Preparation of4-{6-[2-Fluoro-4-(2-isopropoxy-ethylsulfamoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A106)

A mixture of 4-amino-3-fluoro-N-(2-isopropoxy-ethyl)-benzenesulfonamide(116 mg, 0.42 mmol),4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (100 mg, 0.3 mmol), palladium acetate (3 mg, 0.017mmol), biphenyl-2-yl-di-tert-butyl-phosphane (7.1 mg, 0.034 mmol), andsodium t-butoxide (87 mg, 0.90 mmol) in dioxane (2 mL) was heated undermicrowave irradiation for 60 min at 150° C. The crude mixture wasconcentrated in vacuo and purified by HPLC to provide Compound A106 as abrown solid (50 mg, 22%). ¹H NMR (CDCl₃, 400 MHz) δ 1.04 (d, 6H), 1.19(d, 6H), 1.67-1.78 (m, 2H), 1.89-1.99 (m, 5H), 3.05 (t, 2H), 3.30-3.40(m, 4H), 3.42-3.52 (m, 1H), 3.66-3.76 (m, 1H), 4.87 (h, 1H), 5.19-5.38(m, 2H), 7.58 (t, 3H), 7.90-7.98 (s broad, 1H), 8.24 (t, 1H), 8.35 (s,1H). Exact mass calculated for C₂₃H₃₆FN₅O₆S 553.65, found 554.6 (MH⁺).

Example 9.82 Preparation of4-{6-[2,5-Difluoro-4-(N-hydroxycarbamimidoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A107)4-[6-(4-Carbamoyl-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A108)

A mixture of4-[6-(4-cyano-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (TFA salt, 181 mg, 0.332 mmol), hydroxylamine(283.8 mg, 4.08 mmol), and potassium carbonate (283.9 mg, 2.05 mmol in 6mL EtOH/H₂O (2:1 v/v) was stirred at 75° C. for 45 min. The crudemixture was purified by HPLC to give Compound A107 as an oil (TFA salt,111 mg, 58%) and Compound A108 as an oil as a by-product (TFA salt, 74mg, 40%). ¹H NMR of A107 (DMSO-d₆, 400 MHz) δ 1.19-1.20 (d, J=6.32 Hz,6H), 1.61-1.63 (m, 2H), 1.88-1.95 (m, 2H), 2.1 (s, 3H), 3.30-3.37 (m,2H), 3.61-3.63 (m, 2H), 4.75-4.82 (m, J=6.32 Hz, 1H), 5.25-5.29 (m,J=3.79 Hz, 1H), 7.64-7.68 (dd, J=10.36, 6.32 Hz, 1H), 7.72-7.76 (dd,J=11.62, 6.32 Hz, 1H), 8.23 (s, 1H), 8.66 (s, 1H), 9.11 (s, 1H). Exactmass calculated for A107, C₂₁H₂₆F₂N₆O₄ 464.2, found 465.5 (WO and forA108, C₂₁H₂₅F₂N₅O₄ 449.19, found 450.3 (MH⁺).

Example 9.83 Preparation of4-[6-(4-Carbamimidoyl-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A110)

A mixture of Compound A107 (TFA salt, 107.5 mg, 0.186 mmol) and zincdust (242.6 mg, 3.71 mmol) in acetic acid (3 mL) was stirred at 75° C.for 45 min. The crude mixture was purified by HPLC to provide CompoundA110 as a solid (TFA salt, 97.4 mg, 93%). ¹H NMR (CDCl₃, 400 MHz) δ1.24-1.26 (d, J=6.32 Hz, 6H), 1.76-1.78 (m, 2H), 1.97-1.98 (m, 2H), 2.14(s, 3H), 3.37-3.43 (m, 2H), 3.75-3.77 (m, 2H), 4.89-4.96 (m, 1H),5.33-5.37 (m, 1H), 7.16 (s, 1H), 7.48 (s, 1H), 7.59-7.64 (dd, J=10.61,6.82 Hz, 1H), 8.36 (s, 1H), 8.62-8.68 (m, 1H), 10.42 (s, 2H). Exact masscalculated for C₂₁H₂₆F₂N₆O₃ 448.2, found 449.2 (MH⁺).

Example 9.84 Preparation of4-{6-[4-(2-Ethoxy-ethoxy)-2-fluoro-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A111)

Compound A111 was obtained in a similar manner as described in Example9.71 as a brown solid (52 mg, 55%). ¹H NMR (CDCl₃, 400 MHz) δ 1.25 (t,J=7.1 Hz, 3H), 1.25 (d, J=6.3 Hz, 6H), 1.75-1.79 (m, 2H), 1.79 (s, 3H),1.97-2.02 (m, 2H), 3.35-3.42 (m, 2H), 3.61 (q, J=7.1 Hz, 2H), 3.75-3.76(m, 2H), 3.80 (t, J=4.8 Hz, 2H), 4.11 (t, J=4.8 Hz, 2H), 4.93 (sep,J=6.3 Hz, 1H), 5.36-5.40 (m, 1H), 6.72 (d, J=2.02 Hz, 1H), 6.75 (d,J=2.02 Hz, 1H), 7.32 (t, J=8.6 Hz, 1H), 8.30 (s, 1H), 9.41 (s, NH).Exact mass calculated for C₂₄H₃₃FN₄O₅ 476.2, found 477.4 (MH⁺).

Example 9.85 Preparation of4-{6-[2-Fluoro-4-(tetrahydro-pyran-4-yloxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A112)

Compound A112 was obtained in a similar manner as described in Example9.71 as an orange solid (71 mg, 49%). ¹H NMR (CDCl₃, 400 MHz) δ 1.26 (d,J=6.1 Hz, 6H), 1.78-1.86 (m, 4H), 1.90 (s, 3H), 1.99-2.07 (m, 4H),3.37-3.44 (m, 2H), 3.62-3.68 (m, 2H), 3.76-3.79 (m, 2H), 3.98-4.04 (m,2H), 4.49 (m, 1H), 4.94 (sep, J=6.1 Hz, 1H), 5.42-5.44 (m, 1H),6.72-6.74 (m, 1H), 6.74-6.76 (m, 1H), 7.25 (t, J=8.8 Hz, 1H), 8.37 (s,1H), 8.75 (s, NH). Exact mass calculated for C₂₅H₃₃FN₄O₅ 488.2, found489.5 (MH⁺).

Example 9.86 Preparation of4-{6-[2-Fluoro-4-(2-hydroxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A113)

Compound A113 was obtained in a similar manner as described in Example9.71 as an orange solid (76 mg, 84%). ¹H NMR (CDCl₃, 400 MHz) δ 1.25 (d,J=6.3 Hz, 6H), 1.75-1.79 (m, 2H), 1.84 (s, 3H), 1.97-2.02 (m, 2H),3.35-3.42 (m, 2H), 3.74-3.78 (m, 2H), 3.98 (t, J=4.6 Hz, 2H), 4.09 (t,J=4.6 Hz, 2H), 4.93 (sep, J=6.3 Hz, 1H), 5.36-5.40 (m, 1H), 6.72-6.74(m, 1H), 6.75 (s, 1H), 7.35 (t, J=9.1 Hz, 1H), 8.31 (s, 1H), 9.15 (s,NH). Exact mass calculated for C₂₂H₂₉FN₄O₅ 448.2, found 449.3 (MH⁺).

Example 9.87 Preparation of4-{6-[2-Fluoro-4-(pyridin-2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A117)

Compound A117 was obtained in a similar manner as described in Example9.71 as a white solid (11 mg, 11%). Exact mass calculated forC₂₆H₃₀FN₅O₄ 495.2, found 496.3 (MH⁺).

Example 9.88 Preparation of4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-3-methyl-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A118) Step 1: Preparation of2,4-dichloro-3-methyl-pyridine

1.6 M n-Butyl lithium in hexanes (3.75 mL, 6.0 mmol) and anhydrous THF(5 mL) were added to a flame-dried flask under nitrogen atmosphere. Thissolution was cooled to −78 C, 2,4-Dichloro-pyridine was added dropwisewhile stirring and the mixture was stirred at −78 C for 30 min afterwhich time methyliodide (0.374 mL, 6.0 mmol) was added dropwise at −78C. This mixture was stirred at −78 C for 1 h under nitrogen atmosphereafter which time glacial AcOH (0.114 mL, 2.0 mmol) was added to give areaction mixture pH (wet pH paper) of 5-6. The reaction mixture wasdissolved in Et₂O (100 mL), the organic layer was washed with water (10mL), then brine (10 mL), dried with MgSO₄, and the solvent wasevaporated in vacuo to give an oil which was purified by flashchromatography using hexanes:CH₂Cl₂ (50:50 v/v) to hexanes:CH₂Cl₂:EtOAc(50:47:3 v/v/v) to give 2,4-dichloro-3-methyl-pyridine as a white solid(589 mg, 72%). It was noted that 2,4-dichloro-3-methyl-pyridine readilysublimates in vacuo. ¹H NMR (CD₃OD, 400 MHz) δ 8.15 (d, 1H), 7.46 (d,1H), 2.50 (s, 3H). LRMS calculated for C₆H₅Cl₂N, 160.98, found: (MH)⁺161.9.

Step 2: Preparation of4-(2-chloro-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester

4-Hydroxy-piperidine-1-carboxylic acid isopropyl ester (0.496 mL, 2.90mmol) was dissolved in anhydrous dimethylacetamide (DMA, 5 mL), NaH (60%oil dispersion, 116 mg, 2.90 mmol) was added and this mixture wasstirred at 23° C. for 45 min, then this mixture was added dropwise to2,4-dichloro-3-methyl-pyridine, which was dissolved in anhydrous DMA (4mL). This mixture was stirred at 23° C. for 2 h then heated at 50° C.for 15 h, after which time the mixture was diluted with Et₂O (140 mL),washed with water (14 mL), then brine twice (2×14 mL). The organic layerwas separated, dried with MgSO₄, and the solvent was evaporated in vacuoto give an oil which was purified by flash chromatography usinghexanes-EtOAc, 75:25, v/v, then hexanes-EtOAc, 50:50, v/v, to give4-(2-chloro-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester as a solid (223 mg, 27%). ¹H NMR (CDCl₃, 400 MHz) δ 8.09(d, 1H), 6.69 (d, 1H), 4.91 (m, 1H), 4.60 (m, 1H), 3.61 (m, 2H), 3.52(m, 2H), 2.24 (s, 3H), 1.91 (m, 2H), 1.80 (m, 2H), 1.24 d, 6H). LRMScalculated for C₁₅H₂₁ClN₂O₃: 312.12, Found: (MH)⁺ 313.4.

Step 3: Preparation of4-[2-(2-fluoro-4-methanesulfonyl-phenylamino)-3-methyl-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A118)

The free base form of Compound A118 was prepared in a similar manner asdescribed in Example 9.64 with modifications, wherein Pd₂ dba₃, was usedinstead of Pd (OAc)₂, toluene instead of dioxane, and the reaction washeated for 4 h instead of 2 h. Furthermore, no workup was performed andthe reaction mixture was applied directly to flash chromatography usinghexanes:CH₂Cl₂:EtOAc (10:30:60, v/v/v) to give the free base form ofCompound A118 as a solid (166 mg, 51%). ¹H NMR (CDCl₃, 400 MHz) δ 1.24(d, J=6.2 Hz, 6H), 1.86 (m, 2H), 2.00 (m, 2H), 2.05 (s, 3H), 3.05 (s,3H), 3.50 (m, 2H), 3.70 (m, 2H), 4.75 (septet, J=6.3 Hz, 1H), 4.92 (m,1H), 6.74 (d, J=6.1 Hz, 1H), 7.65 (m, 3H), 8.00 (d, J=6.5 Hz, 1H). LRMScalculated for C₂₂H₂₈FN₃O₅S: 465.17, found: 466.5 (MH)⁺.

Example 9.89 Preparation of1-[4-(1-Benzyl-azetidin-3-yloxy)-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone(Compound A61)

Compound A61 was prepared in a manner similar as described in Example9.37 using 1-benzyl-azetidin-3-ol. Exact mass calculated for C₂₂H₂₃N₅O₄S453.15, found 489.6 (MH⁺).

Example 9.90 Preparation of4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester (Compound A60)

A mixture of1-[4-(6-methanesulfonyl-pyridin-3-ylamino)-6-(piperidin-4-yloxy)-pyrimidin-5-yl]-ethanone(48 mg, 0.11 mmol), isobutylchloroformate (14.0 μL, 0.11 mmol), andtriethylamine (45 μL, 0.34 mmol) in DMF (1.0 mL) was heated undermicrowave irradiation for 3 minutes at 80° C. The crude mixture waspurified by HPLC to provide Compound A60 as a white solid (35 mg, 65%).¹H NMR (CDCl₃, 400 MHz) δ 0.97 (d, 6H), 1.82-1.92 (m, 2H), 2.10-2.19 (m,2H), 2.70 (s, 3H), 3.22 (s, 3H), 3.37 (m, 2H), 3.89-3.96 (m, 5H), 5.59(h, 1H), 8.10 (d, 1H), 8.49-8.57 (m, 2H), 8.92 (d, 2H). Exact masscalculated for C₂₂H₂₉N₅O₆S 491.18, found 492.3 (MH⁺).

Example 9.91 Preparation of4-[5-Methyl-6-(4-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A102)

A solution of4-[6-(6-chloro-4-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (223 mg, 0.53 mmol) in 4.5 mL morpholine wasreacted under microwave irradiation at 180° C. for 16 hours. Mixture wasconcentrated and purified by HPLC to give Compound A102 as a white solid(200 mg, 74%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.16-1.18 (d, 6H), 1.64-1.71(m, 2H), 1.89-1.98 (m, 2H), 2.10 (s, 3H), 2.28 (s, 3H), 3.31-3.38 (m,2H), 3.61-3.69 (m, 6H), 3.78-3.80 (m, 4H), 4.77-4.82 (m, 1H), 5.28-5.35(m, 1H), 7.34 (s, 1H), 7.98 (s, 1H), 8.16 (s, 1H). Exact mass calculatedfor C₂₄H₃₄N₆O₄ 470.26, found 471.4 (MH⁺).

Example 9.92 Preparation of4-[5-Methyl-6-(2-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A91)

A solution of4-[6-(6-chloro-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (613 mg, 1.46 mmol) in 15 mL morpholine was reactedunder microwave irradiation at 180° C. for 14 hours. Mixture wasconcentrated and purified by HPLC to give Compound A91 as a white solid(427 mg, 58%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.03-1.05 (d, 6H), 1.51-1.60(m, 2H), 1.78-1.85 (m, 2H), 1.98 (s, 3H), 2.29 (s, 3H), 3.19-3.25 (m,2H), 3.54-3.58 (m, 6H), 3.65-3.67 (m, 4H), 4.65-4.70 (m, 1H), 5.20-5.25(m, 1H), 7.08-7.10 (d, 1H), 7.68-7.71 (d, 1H), 8.07 (s, 1H). Exact masscalculated for C₂₄H₃₄N₆O₄ 470.26, found 471.3 (MH⁺).

Example 9.93 Preparation of4-[5-Amino-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound A120)

Mixture of4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (197 mg, 0.3 mmole), Zn Dust (2.4 mmole, 8 eq) and1 mL of Sat NH₂Cl solution in 2 mL THF and 2 mL H₂O was stirred at roomtemperature for 25 minutes. Zn Dust was filtered off by celite andwashed with ethyl acetate. Crude was purified by column chromatography(Hexane/Ethyl Acetate=1/2, Rf=0.44) to give compound A120 as a yellowoil (100 mg, 71%). ¹H NMR (DMSO-d₆, 400 MHz) δ 1.19 (d, 6H), 1.62-1.68(m, 2H), 1.88-1.93 (m, 2H), 3.23 (s, 3H), 3.33-3.39 (m, 2H), 3.64-3.70(m, 2H), 4.77 (sep, 1H), 5.28-5.29 (m, 1H), 7.68 (d, 1H), 7.77 (d, 1H),7.88 (s, 1H), 8.06 (t, 1H), 8.41 (sb, NH). Exact mass calculated forC₂₀H₂₆FN₅O₅S 467.2, found 468.5 (MH⁺).

Example 9.94 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-1-one(Compound A114) General Procedure of Amide Formation

Dissolve HBTU (1.2 eq, 24 mg) in DMF (0.5 mL), and add butyric acid (1.2eq, 5.8 μL) followed by diisopropyl ethyl amine (2.2 eq, 20.3 μL). Afterapproximately 3 min,(2-fluoro-4-methanesulfonyl-phenyl)-[5-methyl-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine(0.053 mmol) was added, and stirred at room temperature overnight.Reactions were filtered through 0.1 μm syringe filter and purified byPrep-LCMS. Fractions were frozen and lyophilized to solid product. ExactMass: 450.2, found: 451.3 (MH⁺).

Example 9.95 Preparation of1-[4-{6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-1-one(Compound A115)

Compound A115 was prepared in a similar manner as described in Example9.94. Exact Mass: 464.2, found: 465.4 (MH⁺).

Example 9.96 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one(Compound A116)

Compound A116 was prepared in a similar manner as described in Example9.94. Exact Mass: 464.2, found: 465.6 (MH⁺).

Example 9.97 Preparation of4-{6-[2,5-Difluoro-4-(2-methoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound A105)

Compound A105 was obtained in a similar manner as described in Example9.71 as a solid (TFA salt, 222.5 mg, 16%). ¹H NMR (CDCl₃, 400 MHz) δ1.23-1.25 (d, J=6.32 Hz, 6H), 1.72-1.79 (m, 2H), 1.88 (s, 3H), 1.95-2.00(m, 2H), 3.34-3.41 (m, 2H), 3.44 (s, 3H), 3.71-3.77 (m, 4H), 4.14-4.16(m, 2H), 4.87-4.96 (sep, J=6.32 Hz, 1H), 5.31-5.37 (m, 1H), 6.79-6.84(dd, J=11.62, 7.58 Hz, 1H), 7.50-7.55 (dd, J=11.62, 7.58 Hz, 1H), 8.31(s, 1H), 8.56 (s, 1H). Exact mass calculated for C₂₃H₃₀F₂N₄O₅ 480.22,found 481.3 (MH⁺).

Example 10 Syntheses of Compounds of the Present Invention Example 10.1Preparation of4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester (Compound B1)

General Procedure for the Addition of Amine to pyrimidine:(6-Chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (132mg, 0.4 mmole), 4-amino-piperidine-1-carboxylic acid tert-butyl ester(0.4 mmole, 1 eq) and K₂CO₃ (0.4 mmole, 1 eq) were dissolved in DMF, andthe mixture was stirred at 60° C. for 1 hour. Final product wasprecipitated out with water to provide Compound B1 as a yellow solid(152 mg, 77%). ¹H NMR (400 MHz CDCl₃) δ (ppm): 10.8 (s, 1H), 9.18 (d,1H), 8.17 (s, 1H), 7.90 (d, 2H), 7.85 (d, 2H), 4.39-4.32 (m, 1H), 4.02(m, 2H), 3.01 (s, 3H), 2.95-2.90 (m, 2H), 2.00 (m, 2H), 1.57-1.50 (m,2H), 1.46 (s, 9H). Exact mass calculated for C₂₁H₂₈N₆O₆S 492.18, LCMS(ESI) m/z 493.4 (M+H⁺, 100%).

Example 10.2 Preparation ofN-(4-Methanesulfonyl-phenyl)-5-nitro-N′-piperidin-4-yl-pyrimidine-4,6-diamine(Compound B2)

General Deprotection Procedure: A mixture of Compound B1 and 4 M HCl indioxane was stirred at 40° C. overnight and concentrated. Excess HCl wasevaporated with isopropyl alcohol provided Compound B2 as yellow solid(261 mg, 97%). ¹H NMR (400 MHz CDCl₃) δ (ppm): 10.9 (s, 1H), 8.96 (d,2H), 8.17 (s, 1H), 7.84 (d, 4H), 4.40-4.37 (m, 1H), 3.25-3.22 (m, 2H),3.16 (s, 3H), 3.01-2.93 (m, 2H), 2.04-2.01 (m, 2H), 1.88-1.78 (m, 2H).Exact mass calculated for C₁₆H₂₀N₆O₄S 392.13, LCMS (ESI) m/z 393.1(M+H⁺, 100%).

Example 10.3 Preparation of1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-ethanone(Compound B3)

General Procedure of Acetylating: Mixture of B2 and acetyl chloride wasstirred at 180° C. for 2 hours in microwave to provide Compound B3 asyellow solid (10 mg, 18%). ¹H (400 MHz CDCl₃) δ (ppm): 9.06 (d, 1H),8.07 (s, 1H), 7.78 (d, 2H), 7.70 (d, 2H), 4.42-4.37 (m, 1H), 4.35-4.30(m, 1H), 3.74-3.71 (m, 1H), 3.19-3.13 (m, 1H), 2.89 (s, 3H), 2.82-2.76(m, 1H), 2.04 (s, 3H), 2.00-1.97 (m, 2H), 1.46-1.37 (m, 2H). Exact masscalculated for C₁₈H₂₂N₆O₅S 434.14, LCMS (ESI) m/z 435.4 (M+H⁺, 100%).

Example 10.4 Preparation of1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-2,2-dimethyl-propan-1-one(Compound B4). Compound B4 was prepared in a similar manner as describedabove as yellow solid (7 mg, 11%). ¹H NMR (400 MHz CDCl₃) δ (ppm): 9.16(d, 1H), 8.17 (s, 1H), 7.89 (d, 2H), 7.82 (d, 2 H), 4.48-4.42 (m, 1H),4.35-4.32 (m, 2H), 3.07-3.04 (m, 2H), 3.00 (s, 3H), 2.10-2.08 (m, 2H),1.55-1.46 (m, 2H), 1.24 (s, 9H). Exact mass calculated for C₂₁H₂₈N₆O₅S476.18, LCMS (ESI) m/z 477.3 (M+H⁺, 100%).4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (Compound B5)

Compound B5 was prepared in a similar manner as described in Example10.1 as a solid (24 mg, 23%). Exact mass calculated for C₂₆H₃₈FN₅O₄S535.2, found 536.4 (MH⁺).

Example 11 Syntheses of Compounds of the Present Invention Example 11.1Preparation of4-[6-(2-Fluoro-4-morpholin-4-yl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C3)

A mixture of4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C130, 500 mg, 1.07 mmole), morpholine(121 mg, 1.39 mmole), palladium acetate (3 mg, 0.011 mmole),biphenyl-2-yl-di-tert-butyl-phosphane (4 mg, 0.012 mmole) and sodiumt-butoxide (257 mg, 2.14 mmole) in dioxane (3 mL) was heated undermicrowave irradiation at 150° C. for 1 hours. The crude mixture waspurified by HPLC to provide Compound C3 as a yellow oil (235 mg, 46%).¹H NMR (CDCl₃, 400 MHz) δ 1.28 (d, J=6.3 Hz, 6H), 1.81-1.85 (m, 2H),1.99-2.04 (m, 2H), 2.20 (s, 3H), 3.44-3.47 (m, 2H), 3.49-3.51 (m, 4H),3.73-3.78 (m, 2H), 4.08-4.10 (m, 2H), 4.95 (sep, J=6.3 Hz, 1H),5.35-5.37 (m, 1H), 7.25 (d, J=10.1 Hz, 2H), 7.32 (t, J=8.6 Hz, 1H), 8.26(s, 1H). Exact mass calculated for C₂₄H₃₁FN₄O₅ 474.2, found 475.4 (MH⁺).

Example 11.2 Preparation of(6-Amino-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone(Compound C5)

6-Amino-nicotinic acid (21.5 mg, 0.155 mmol), HATU (59 mg, 0.155 mmol)and triethylamine (0.05 mL, 0.359 mmol) were mixed in DMF and stirred atrt for 20 min.4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidinewas then added and the mixture stirred at rt for 2 h. The crude waspurified by HPLC to afford Compound C5 as a yellow solid (67 mg, 90.7%).¹H NMR (CDCl₃, 400 MHz) δ 1.88-1.87 (m, 2H), 1.99-2.01 (m, 2H), 2.15 (s,3H), 3.03 (s, 3H), 3.58-3.60 (m, 2H), 3.77-3.78 (m, 2H), 5.37-5.41 (m,1H), 6.78-6.82 (d, 1H), 7.33-7.38 (m, 1H), 7.69-7.74 (m, 2H), 7.87-7.96(m, 2H), 8.14 (s, 1H). Exact mass calculated for C₂₃H₂₄FN₅O₅S 501.15,found 502.4 (MH⁺).

Example 11.3 Preparation of4-[5-Ethyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C6) Step 1: Preparation of4-(6-chloro-5-ethyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester

To a solution of 4,6-dichloro-5-ethyl-pyrimidine (1 g, 5.65 mmol) and4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (1.05 g, 5.65mmol) in dry THF under nitrogen at 0° C., potassium tert-butoxide (1Msolution in THF, 6.78 mL) was added dropwise. The reaction was stirredat rt for 30 min. The mixture was quenched with water and extracted withEtOAc (3×). The organic layer was washed with water, sat. NH₄Cl andbrine, followed by drying over sodium sulfate and concentration undervacuo. The resulting oil was purified by HPLC to afford4-(6-chloro-5-ethyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (0.74 g, 39.8%) as a colorless oil. Exact masscalculated for C₁₅H₂₂ClN₃O₃ 327.13, found 328.2 (MH⁺).

Step 2: Preparation of4-[5-ethyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C6)

4-(6-Chloro-5-ethyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (50 mg, 0.152 mmol), 2-fluoro-4-methanesulfonyl-phenol(43.5 mg, 0.228 mmol) and sodium hydride (60% dispersion in mineral oil,7.28 mg, 0.182 mmol) were dissolved in DMSO (2 mL) and the mixture washeated under microwave irradiation for 1 h at 150° C. The crude wasquenched with water and extracted with ethyl acetate. The organic layerwas concentrated and the residue was purified by HPLC to afford CompoundC6 (20.3 mg, 27.6%) as a white powder. ¹H NMR (CDCl₃, 400 MHz) δ 1.13(t, J=7.33 Hz, 3H), 1.18 (d, J=6.32 Hz, 6H), 1.72-1.76 (m, 2H),1.89-1.94 (d, 2H), 2.64 (q, J=7.33 Hz, 2H), 3.02 (s, 3H), 3.35-3.41 (m,2H), 3.63-3.66 (m, 2H), 4.85-4.88 (m, 1H), 5.25-5.32 (m, 1H), 7.35-7.37(m, 1H), 7.69-7.74 (m, 2H), 8.13 (s, 1H). Exact mass calculated forC₂₂H₂₈FN₃O₆S 481.17, found 482.4 (MH⁺).

Example 11.4 Preparation of4-{6-[6-(2-Isopropoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C10)

A mixture of4-[6-(6-chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (60 mg, 0.143 mmol), palladium acetate (12 mg, 0.05mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo [3,3,3]undecane (5 mL, 0.015 mmol), 2-isopropoxy-ethylamine (35 μL, 0.28 mmol),and sodium tert-butoxide in 1.5 mL dioxane were heated under microwaveirradiation for 1 hour at 120° C. Mixture was purified by HPLC to giveCompound C10 as a tanned solid (TFA salt, 44.1 mg, 51%). ¹H NMR(MeOH-d₄, 400 MHz) δ 1.01-1.03 (d, 6H), 1.09-1.11 (d, 6H), 1.58-1.63 (m,2H), 1.82-1.90 (m, 2H), 2.05 (s, 3H), 2.20 (s, 3H), 3.22-3.30 (m, 2H),3.46-3.63 (m, 7H), 4.70-4.75 (m, 1H), 5.21-5.27 (m, 1H), 6.82-6.85 (d,1H), 7.60-7.62 (d, 1H), 8.01 (s, 1H). Exact mass calculated forC₂₅H₃₇N₅O₅ 487.28, found 488.6 (MH⁺).

Example 11.5 Preparation of4-{6-[6-(2-Hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C12)

A mixture of4-[6-(6-chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (835 mg, 1.98 mmol) and potassium carbonate (305mg, 2.2 mmol) in 3 mL of 2-mercapto-ethanol was stirred in microwave at80° C. After 17 hours, mixture was continued to be stirred at 100° C.for 30 minutes and then 120° C. for 30 minutes. Mixture was purified byHPLC and column chromatography (hexane/AcOEt) to give Compound C12 as awhite solid (16.4 mg, 2%). ¹H NMR (CDCl₃, 400 MHz) δ 1.07-1.09 (d, J=6.3Hz, 6H), 1.68-1.78 (m, 2H), 1.90-1.99 (m, 2H), 2.12 (s, 3H), 2.29 (s,3H), 3.23-3.25 (t, J=5.1 Hz, 2H), 3.32-3.38 (m, 2H), 3.68-3.71 (m, 2H),3.91-3.94 (t, J=4.9 Hz, 2H), 4.84-4.90 (m, 1H), 5.24-5.30 (m, 1H),7.12-7.21 (m, 2H), 8.12 (s, 1H). Exact mass calculated for C₂₂H₃₀N₄O₅S462.19, found 463.3 (MH⁺).

Example 11.6 Preparation of4-[5-Methyl-6-(2-methyl-6-pentyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C15)

To a solution of4-[6-(6-chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (75.1 mg, 0.140 mmol) and iron (III)acetylacetonate (3.1 mg, 0.0088 mmol) in 1 mL THF and 0.1 mL NMP, 2Mpentylmagnesium bromide solution in diethylether (135 μl, 0.275 mol)were added. After stirring at room temperature for several hours,mixture was purified by HPLC to give Compound C15 as an oil (TFA salt,1.8 mg, 2%). Exact mass calculated for C₂₅H₃₆N₄O₄ 456.27, found 457.4(MH⁺).

Example 11.7 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-2-one(Compound C93)

4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidinehydrochloride salt (42 mg, 0.1 mmol), 1-bromo-butan-2-one (0.1 mmol, 1eq), and triethylamine (0.2 mmol, 2 eq) were dissolved in DMF (1 mL) andthen stirred at room temperature overnight. The crude was filtered andthen purified via prep-LCMS 5-95% to provide Compound C93 as an oil(39.6 mg, 88%). Exact mass calculated for C₂₁H₂₆FN₃O₅S 451.2, found452.3 (MH⁺).

Example 11.8 Preparation of4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(2-pyridin-3-yl-ethyl)-piperidin-4-yloxy]-pyrimidine(Compound C18)

A mixture of4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine(100 mg, 0.24 mmol), toluene-4-sulfonic acid 2-pyridin-3-yl-ethyl ester(133 mg, 0.48 mmol), and triethylamine (167 μL, 1.2 mmol) in DMF (2 mL)was heated under microwave irradiation for 60 min at 150° C. The crudemixture was concentrated in vacuo and purified by HPLC to provideCompound C18 as an oil (15 mg, 13%). ¹H NMR (CDCl₃, 400 MHz) δ 2.15 (s,3H), 2.18-2.38 (m, 4H), 3.04 (s, 3H), 3.07-3.22 (m, 2H), 3.29-3.43 (m,4H), 3.44-3.65 (m, 2H), 5.43-5.51 (m, 1H), 7.36 (t, 1H), 7.67-7.79 (m,3H), 8.11 (s, 1H), 8.35 (d, 1H), 8.58 (d, 1H), 8.91 (s, 1H). Exact masscalculated for C₂₄H₂₇FN₄O₄S 486.56, found 487.4 (MH⁺).

Example 11.9 Preparation of2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone(Compound C21)

Compound C21 was prepared using a similar procedure as described inExample 11.7 and purified by preparative HPLC. ¹H NMR (CDCl₃, 400 MHz) δ2.22 (s, 3H), 2.33 (m, 2H), 2.48 (m, 2H), 3.14 (s, 3H), 3.69 (m, 4H),4.78 (s, 2H), 5.58 (m, 1H), 7.34 (d, 2H), 7.44 (t, 1H), 7.79 (m, 2H),7.99 (d, 2H), 8.22 (s, 1H). Exact mass calculated for C₂₆H₂₅F₄N₃O₆S583.14, found 584.3 (MH⁺).

Example 11.10 Preparation of4-{6-[6-(2-Methoxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C24)

A solution of4-{6-[6-(2-methoxy-ethylsulfanyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (8.8 mg, 0.0185 mmol) in 1 mL methylene chloridewas cooled in an ice bath and 3-chloroperoxybenzoic acid (9.4 mg, 0.038mmol) was added. After stirring for one hour in an ice-bath, mixture wasquenched with a aqueous bicarbonate solution and purified by HPLC togive Compound C24 as a white solid (TFA salt, 7.6 mg, 66%). ¹H NMR(MeOH-d₄, 400 MHz) δ 1.22-1.23 (d, 6H), 1.70-1.80 (m, 2H), 1.95-2.02 (m,2H), 2.20 (s, 3H), 2.43 (s, 3H), 3.14 (s, 3H), 3.35-4.45 (m, 2H),3.64-3.66 (t, J=5.9 Hz, 3H), 3.70-3.76 (m, 4H), 4.82-4.88 (m, 1H),5.35-5.39 (m, 1H), 7.72-7.75 (d, J=8.36 Hz, 1H), 8.13 (s, 1H). Exactmass calculated for C₂₃H₃₂N₄O₆S 508.20, found 509.4 (MH⁺).

Example 11.11 Preparation of4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine(Compound C27) Step 1: Preparation of N-hydroxy-isobutyramidine

A solution of isobutyronitrile (276 g, 4.0 mol) in EtOH (2.0 L) wascombined with hydroxylamine (50% aqueous solution, 1.1 L, 16 mol), andrefluxed for 5 h. The solvent was then removed in vacuo, and theresidual water was azeotropically removed with toluene. The residue wasthen taken up in CH₂Cl₂, dried over MgSO₄, and the solvent was removedto afford a white solid (402 g, 98% yield). ¹H NMR (CDCl₃) δ 7.94 (br s,1 H), 4.55 (br s, 2 H), 2.47 (m, 1 H), 1.20 (d, 6 H, J=7.1 Hz).

Step 2: Preparation of 1-cyano-4-hydroxypiperidine

A 5-liter, 3-neck flask was equipped with mechanical stirring, a refluxcondenser, and a powder addition funnel. Sodium bicarbonate (840 g, 10mmol) was added via the powder funnel while stirring, then water (ca.300-400 mL) was gradually added while vigorously stirring to form athick, uniform slurry. The flask was then placed in an ice bath, and asolution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH₂Cl₂ (1.0 L) wasadded, and the contents were vigorously mixed while cooling. A solutionof cyanogen bromide (640 g, 6.0 mol) in CH₂Cl₂ (600 mL) was added in adropwise fashion over 2 h, and stirring was continued for an additional30 min. The ice bath was removed, and the mechanical stirrer wasreplaced by a magnetic stirrer, and the reaction mixture was stirred for16 h. The flask was once again placed under mechanical stirring, andsodium carbonate (100 g) was added in order to ensure completeneutralization. MgSO₄ (500 g) was added, and vigorous stirring wascontinued for 15 min. The resulting suspension was filtered, rinsingwith CH₂Cl₂ (2.0 L). A light amber, viscous oil was obtained uponsolvent removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield.¹H NMR (CDCl₃) δ 3.80 (m, 1 H), 3.39 (m, 2 H), 3.05 (m, 2 H), 1.87 (m, 2H), 1.70 (br s, 1 H), 1.62 (m, 2 H), MS m/z 212.1 (M⁺).

Step 3: Preparation of1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol

In a variation of the method described by Yarovenko et al, (Bull. Acad.Sci. USSR, Div. Chem. Sci. 1991, 40, 1924) ZnCl₂ (1 N in ether, 120 mL,120 mmol) was added in a dropwise fashion over 15 min to a magneticallystirred solution of N-hydroxy-isobutyramidine (12.2 g, 120 mmol) and4-hydroxy-piperidine-1-carbonitrile (12.6 g, 100 mmol) in ethyl acetate(500 mL). Precipitate formed immediately upon addition, and at a pointthe stirring bar became immobilized in the matrix, requiring thereaction to be manually shaken for the remainder of addition. Afterstanding for 15 min, the supernatant was decanted and filtered, and theresidue was rinsed twice with ether, furnishing a hard white precipitatewhich was collected by filtration. This material was taken up in conc.HCl (50 mL), diluted to 4 N with EtOH (100 mL), and refluxed for 1 h.Upon cooling, a white precipitate was removed by filtration, then thefiltrate was reduced to 50 mL and diluted with 100 mL water. SolidNa₂CO₃ was added until the mixture was basic, CH₂Cl₂ was added, and theresulting mixture was filtered, rinsing with CH₂Cl₂. The organic extractwas separated, dried over MgSO₄, and the solvent was removed to afford aviscous, amber oil as1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (15.0 g, 71%yield): ¹H NMR (CDCl₃) δ 3.95 (m, 3 H), 3.37 (m, 2 H), 2.88 (m, 1 H),2.34 (br s, 1 H), 1.93 (m, 2 H), 1.63 (m, 2 H), 1.28 (d, 6 H, J=7.1 Hz),MS m/z 212.3 (M⁺).

Step 4: Preparation of4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine

To a solution of 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol(3.65 g, 17 mmol) and 4,6-dichloro-5-methylpyrimidine (2.83 g, 17 mmol)in THF (70 mL), 1M potassium-t-butoxide in THF (16 mL, 16 mmol) wasadded dropwise. The mixture was stirred at room temperature for 10 min.The crude mixture was purified by column chromatography on silica gelwith hexane/ethyl acetate (3:1 v/v) to provide4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidineas a solid (4.15 g, 71%). Exact mass calculated for C₁₅H₂₀ClN₅O₂337.13,found 338.2 (MH⁺).

Step 5: Preparation of4-(2-fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine(Compound C27)

A mixture of4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine(756 mg, 2.24 mmol), 2-fluoro-4-methanesulfonyl-phenol (635 mg, 3.33mmol), and sodium hydride, 60% dispersion in mineral oil (232 mg, 5.81mmol) in DMAA (30 mL) was divided into two 20 mL microwave vials andheated under microwave irradiation at 150° C. for 1 hour. The crudemixture was purified by HPLC to provide Compound C27 as a solid (TFAsalt, 75.5 mg, 5.6%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28-1.31 (d, J=6.32 Hz,6H), 1.96-2.02 (m, 2H), 2.08-2.15 (m, 2H), 2.20 (s, 3H), 2.91-2.98 (m,1H), 3.09 (s, 3H), 3.65-3.71 (m, 2H), 3.82-3.89 (m, 2H), 5.42-5.46 (m,1H), 7.41-7.44 (m, 1H), 7.77-7.81 (m, 2H) 8.21 (s, 1H). Exact masscalculated for C₂₂H₂₆FN₅O₅S 491.16, found 492.3 (MH⁺).

Example 11.12 Preparation of4-(6-{2-Fluoro-4-[(2-hydroxy-ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound C31)

Compound C31 was obtained in a similar manner as described in Example11.36 as a solid (39 mg, 24%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.20 (d, 6H),1.63-1.72 (m, 2H), 1.89-1.99 (m, 2H), 2.11 (s, 3H), 3.19-3.26 (m, 3H),3.33-3.43 (m, 2H), 3.44-3.56 (m, 4H), 3.64-3.73 (m, 2H), 4.80 (s, 1H),5.30 (h, 1H), 7.02-7.16 (m, 3H), 8.03 (s, 1H). Exact mass calculated forC₂₄H₃₁FN₄O₆ 490.52, found 491.4 (MH⁺).

Example 11.13 Preparation of4-[6-(5-Iodo-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C34)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.02 g, 3.25 mmol), 2-hydroxy-5-iodopyridine, andpotassium carbonate (903 mg, 6.53 mmol) in 15 mL DMF were heated undermicrowave irradiation for 1 hour at 150° C. Mixture was purified by HPLCto give Compound C34 (TFA salt, 177 mg, 9%) as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 1.24-1.25 (d, 6H), 1.75-1.83 (m, 2H), 1.97-2.03 (m,2H), 2.20 (s, 3H), 3.40-3.45 (m, 2H), 3.71-3.79 (m, 2H), 4.91-4.97 (m,1H), 5.33-5.39 (m, 1H), 6.93-6.95 (d, 1H), 8.04-8.07 (dd, 1H), 8.31 (s,1H), 8.51-8.52 (d, 1H). Exact mass calculated for C₁₉H₂₃IN₄O₄ 498.08,found 499.2 (MH⁺).

Example 11.14 Preparation of4-(6-{2-Fluoro-4-[N-(2-isopropoxy-ethyl)-carbamimidoyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound C36) and4-[6-(4-Carbamoyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C139) Step 1: Preparation of4-[6-(2-fluoro-4-phenylsulfanylcarbonimidoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester

A mixture of4-[6-(4-cyano-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (TFA salt, 109 mg, 0.21 mmol) and thiophenol (27μl, 0.21 mmol) in Et₂O (1 mL) was stirred in an ice-bath under HBratmosphere for 30 min. The crude compound was used for the next stepwithout further purification. Exact mass calculated for C₂₇H₂₉FN₄O₄S524.19, found 525.3 (MH⁺).

Step 2: Preparation of4-(6-{2-Fluoro-4-[N-(2-isopropoxy-ethyl)-carbamimidoyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound C36) and4-[6-(4-Carbamoyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C139)

A mixture of4-[6-(2-fluoro-4-phenylsulfanylcarbonimidoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (108.4 mg, 0.21 mmol) and 2-aminoethyl isopropylether (101 μl, 0.83 mmol) in MeOH (2 mL) was stirred at room temperaturefor 30 min. Additional 2-aminoethyl isopropyl ether (2 mL, 16.3 mmol)was added and the mixture was stirred under 70° C. for 10 min. The crudemixture was purified by HPLC to provide Compound C36 as a solid (TFAsalt, 19.6 mg, 15%). and Compound C139 in solid as a by-product (TFAsalt, 23.7 mg, 21%). Compound C36: ¹H NMR (CDCl₃, 400 MHz) δ 1.13-1.20(m, 6H), 1.26-1.27 (d, 6H), 1.78-1.80 (m, 2H), 1.98-1.99 (m, 2H),2.19-2.20 (d, 3H), 2.82 (s, 5H), 3.39-3.46 (m, 3H), 3.68-3.79 (m, 4H),4.92-4.95 (m, 1H), 5.34-5.35 (m, 1H), 7.38-7.44 (m, 1H), 7.68-7.71 (t,1H), 8.13-8.19 (d, 1H). Exact mass calculated for Compound C36,C₂₆H₃₆FN₅O₅ 517.27, found 518.5 (MH⁺) and for Compound C139, exact masscalculated for C₂₁H₂₅FN₄O₅432.18, found 433.1 (MH⁺).

Example 11.15 Preparation of4-[6-(4-Carboxy-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C38)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (300 mg, 0.96 mmol), 2 (150 mg, 0.96 mmol) and potassiumcarbonate (160 mg, 1.15 mmol) in DMSO was heated under microwave for 4hrs at 160° C. The mixture was purified through HPLC to afford CompoundC38 (200 mg, 48%) as a solid and Compound C9 as a by product. CompoundC38: ¹H NMR (MeOH-d₄, 400 MHz) δ 1.15 (d, 6H), 1.64-1.67 (m, 2H),1.88-1.92 (m, 2H), 2.09 (s, 3H), 3.29-3.31 (m, 2H), 3.62-3.66 (m, 2H),4.72-4.78 (m, 1H), 5.25-5.28 (m, 1H), 7.23 (t, 1H), 7.70 (d, 1H), 7.77(d, 1H), 8.02 (s, 1H). Exact mass calculated for C₂₁H₂₄FN₃O₆ 433.2,found 434.3 (MH⁺). Compound C9: Exact mass calculated for C₂₀H₂₄FN₃O₄389.2, found 390.3 (MH⁺).

Example 11.16 Preparation of4-(4-Bromo-2-fluoro-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine(Compound C40)

A mixture of4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine(1.51 g, 4.46 mmol), potassium carbonate (1.25 g, 9.03 mmol), and4-bromo-2-fluorophenol (1.11 g, 5.82 mmol) in 15 mL DMF was heated inmicrowave for 1 hour at 150° C. The mixture was purified by columnchromatography on silica gel with hexane/ethyl acetate (3:1 v/v) to giveCompound C40 as an oil (1.05 g, 48%). ¹H NMR (CDCl₃, 400 MHz) δ1.20-1.22 (d, 6H), 1.83-1.91 (m, 2H), 1.98-2.05 (m, 2H), 2.11 (s, 3H),2.77-2.87 (m, 1H), 3.53-3.59 (m, 2H), 3.74-3.80 (m, 2H), 5.31-5.36 (m,1H), 6.99-7.03 (m, 1H), 7.22-7.29 (m, 2H), 8.13 (s, 1H). Exact masscalculated for C_(2i)H₂₃BrFN₅O₃ 491.1, found 492.4 (MH⁺).

Example 11.17 Preparation of4-[6-(5-Methanesulfonyl-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C42)

A mixture of4-[6-(5-iodo-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (TFA salt, 35.1 mg, 0.07 mmol), sodiummethanesulfinate (21.4 mg, 0.21 mmol), copper (I)trifluoromethanesulfonate benzene complex (3.5 mg, 0.007 mmol), andN,N′-dimethyl-ethane-1,2-diamine in 1.5 mL DMSO were heated undermicrowave irradiation for 30 minutes at 160° C. Mixture was purified byHPLC to give Compound C42 as a white solid (TFA salt, 11.5 mg, 30%). ¹HNMR (MeOH-d₄, 400 MHz) δ 1.21-1.22 (d, 6H), 1.71-1.79 (m, 2H), 1.96-2.07(m, 5H), 3.16 (s, 3H), 3.35-4.42 (m, 2H), 3.80-3.87 (m, 2H), 4.80-4.86(m, 1H), 5.38-5.42 (m, 1H), 7.32-7.34 (d, 1H), 8.29 (s, 1H), 8.35-8.37(dd, 1H), 8.69 (s, 1H). Exact mass calculated for C₂₀H₂₆N₄O₆S 450.16,found 451.4 (MH⁺).

Example 11.18 Preparation of4-{6-[6-(2-Hydroxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C43)

To a solution of4-{6-[6-(2-methoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (TFA salt, 87 mg, 0.152 mmol) in methylenechloride, trimethylsilyl iodide (300 μl, 1.5 mmol) was added. Afterstirring for 3 hours at room temperature, mixture was quenched withmethanol and purified by HPLC to give Compound C43 as a white solid (TFAsalt, 40.6 mg, 48%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.22-1.23 (d, J=6.2 Hz,6H), 1.69-1.77 (m, 2H), 1.94-2.02 (m, 2H), 2.17 (s, 3H), 2.31 (s, 3H),3.32-3.40 (m, 2H), 3.52-3.55 (t, J=5.1 Hz, 2H), 3.70-3.80 (m, 4H),4.84-4.88 (m, 1H), 5.34-5.38 (m, 1H), 6.93-6.95 (d, J=9.6 Hz, 1H),7.70-7.73 (d, J=9.6 Hz, 1H), 8.13 (s, 1H). Exact mass calculated forC₂₂H₃₁N₅O₅ 445.23, found 446.3 (MH⁺).

Example 11.19 Preparation of4-[5-Cyclopropyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C44) Step 1: Preparation of4-(6-chloro-5-cyclopropyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester

To a solution of 4,6-dichloro-5-cyclopropyl-pyrimidine (700 mg, 3.70mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (636.6mg, 3.70 mmol) in dry THF under nitrogen at 0° C., potassiumtert-butoxide (1M solution in THF, 4.45 mL) was added dropwise. Thereaction was stirred at rt for 30 min. The mixture was quenched withwater and extracted with EtOAc (3×). The organic layer was washed withwater, sat. NH₄Cl and brine, followed by drying over sodium sulfate andconcentration under vacuo. The resulting oil was purified by flashchromatography (0-20% EtOAc/Hexanes) to afford4-(6-chloro-5-cyclopropyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (0.927 g, 73.7%) as colorless oil. Exact masscalculated for C₁₆H₂₂ClN₃O₃ 339.13, found 340.3 (MH⁺).

Step 2: Preparation of4-[5-Cyclopropyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C44)

4-(6-Chloro-5-cyclopropyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (200 mg, 0.588 mmol),2-fluoro-4-methanesulfonyl-phenol (168 mg, 0.883 mmol) and sodiumhydride (60% dispersion in mineral oil, 53 mg, 1.325 mmol) weredissolved in DMSO (2 mL) and the mixture stirred under Nitrogen for 10min at rt. The mixture was then heated under microwave irradiation for 1h at 150° C. The crude was quenched with water and extracted with EtOAc(3×). The organic layer was concentrated and the residue was purified byHPLC to afford Compound C44 (51 mg, 14.3%) as oil. ¹H NMR (CDCl₃, 400MHz) δ 0.90-0.97 (m, 2H), 1.01-1.06 (m, 2H), 1.23-1.27 (d, J=6.06 Hz,6H), 1.76-1.91 (m, 2H), 1.92-2.02 (m, 2H), 3.08 (s, 3H), 3.46-3.55 (m,2H), 3.63-3.72 (m, 2H), 4.87-4.98 (m, 1H), 5.32-5.39 (m, 1H), 7.36-7.42(m, 1H), 7.73-7.80 (m, 2H), 8.17 (s, 1H). Exact mass calculated forC₂₃H₂₈FN₃O₆S 493.17, found 494.5 (MH⁺).

Example 11.20 Preparation of4-{6-[6-(2-Methanesulfonyl-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C46)

Using a similar procedure as described in Example 11.4 for thepreparation of Compound C10, Compound C46 was obtained as a tanned solid(TFA salt, 27.0 mg, 30%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.05-1.06 (d, 6H),1.64-1.72 (m, 2H), 1.88-1.97 (m, 2H), 2.12 (s, 3H), 2.27 (s, 3H), 2.98(s, 3H), 3.29-3.37 (m, 2H), 3.43-3.46 (t, 2H), 3.65-3.71 (m, 2H),3.86-3.89 (t, 2H), 4.78-4.82 (m, 1H), 5.29-5.33 (m, 1H), 6.90-6.92 (d,1H), 7.72-7.74 (d, 1H), 8.07 (s, 1H). Exact mass calculated forC₂₃H₃₃N₅O₆S 507.22, found 508.6 (MH⁺).

Example 11.21 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-hexan-1-one(Compound C121)

4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine(42 mg, 0.1 mmol), 5-methyl-hexanoic acid (0.12 mmol, 1.2 eq), HATU(0.12 mmol, 1.2 eq), and triethylamine (0.2 mmol, 2 eq) were dissolvedin DMF (1 mL), and then stirred at room temperature for 1 hour. Thecrude was filtered and then purified via prep-LCMS 5-95% to provideCompound C121 as a white powder (28.2 mg, 57%). Exact mass calculatedfor C₂₄H₃₂FN₃O₅S 493.2, found LCMS (ESI) m/z 494.5 (MH⁺).

Example 11.22 Preparation of4-{6-[6-(2-Methoxy-ethylsulfanyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C56)

To a solution of compound C12 (15 mg, 0.0324 mmol) in 1 mL THF, sodiumhydride dispersion (8 mg, 0.2 mmol) was added. After 10 minutes, methyliodide (20 μl, 0.32 mmol) was added and mixture was stirred at roomtemperature for 17 hours. Mixture was purified by column chromatography(AcOEt/hexane) to give Compound C56 as white solid (10.1 mg, 65%). ¹HNMR (CDCl₃, 400 MHz) δ 1.25-1.27 (d, J=6.3 Hz, 6H), 1.75-1.85 (m, 2H),1.95-2.05 (m, 2H), 2.19 (s, 3H), 2.34 (s, 3H), 3.37-3.45 (m, 7H),3.65-3.68 (t, J=6.7 Hz, 2H), 3.75-3.81 (m, 2H), 4.91-4.97 (m, 1H),5.32-5.36 (m, 1H), 7.07-7.09 (d, J=8.4 Hz, 1H), 7.22-7.20 (d, J=8.4 Hz,1H), 8.19 (s, 1H). Exact mass calculated for C₂₃H₃₂N₄O₅S 476.21, found477.4 (MH⁺).

Example 11.23 Preparation of1-(2,5-Dimethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone(Compound C60)

Compound C60 was prepared using a similar procedure as described inExample 11.7 and was obtained as an oil (35.9 mg, 64%). Exact masscalculated for C₂₇H₃₀FN₃O₇S 559.2, found LCMS (ESI) m/z 560.4 (MH⁺).

Example 11.24 Preparation of4-[6-(6-Chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C65)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.03 g, 3.27 mmol), 6-chloro-2-methyl-pyridin-3-ol (470mg, 3.27 mmol), and potassium carbonate (903 mg, 6.53 mmol) in 15 mL DMFwere heated in microwave for 1 hour at 150° C. The mixture was purifiedto give Compound C65 as a white solid (0.975 g, 71%). ¹H NMR (CDCl₃, 400MHz) δ 0.92-0.94 (d, 6H), 1.74-1.82 (m, 2H), 1.95-2.02 (m, 2H), 2.19 (s,3H), 2.47 (s, 3H), 3.39-3.45 (m, 2H), 3.74-3.79 (m, 2H), 4.91-4.97 (m,1H), 5.33-5.36 (m, 1H), 7.21-7.23 (d, 1H), 7.36-7.38 (d, 1H), 8.19 (s,1H). Exact mass calculated for C₂₀H₂₅ClN₄O₄ 420.16, found 421.3 (MH⁺).

Example 11.25 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one(Compound C78)

Compound C78 was prepared using a similar procedure as described inExample 11.7 and was obtained as an oil (26 mg, 54%). Exact masscalculated for C₂₃H₃₀FN₃O₅S 479.2, found LCMS (ESI) m/z 480.4 (WO.

Example 11.26 Preparation of2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone(Compound C22)

Compound C22 was prepared using a similar procedure as described inExample 11.7 and was purified by preparative HPLC. ¹H NMR (CDCl₃, 400MHz) δ 2.24 (s, 3H), 2.29 (m, 1H), 2.42 (m, 1H), 2.57 (m, 2H), 3.11 (s,3H), 3.51 (m, 2H), 3.77 (m, 2H), 4.98 (s, 2H), 5.60 (m, 1H), 7.43 (t,1H), 7.61 (m, 1H), 7.82 (m, 2H), 7.91 (m, 1H), 8.23 (m, 1H), 8.67 (m,1H). Exact mass calculated for C₂₄H₂₅FN₄O₅S 500.15, found 501.3 (MH⁺).

Example 11.27 Preparation of2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-fluoro-phenyl)-ethanone(Compound C16)

Compound C16 was prepared using a similar procedure as described inExample 11.7 and purified by preparative HPLC. ¹H NMR (CDCl₃, 400 MHz) δ2.31 (s, 3H), 2.34 (m, 2H), 2.39 (m, 2H), 3.11 (s, 3H), 3.68 (m, 4H),4.78 (s, 2H), 5.59 (m, 1H), 7.36 (m, 1H), 7.46 (m, 1H), 7.52 (m, 1H),7.63 (m, 1H), 7.71 (m, 1H), 7.82 (m, 2H), 8.22 (s, 1H). Exact masscalculated for C₂₅H₂₅F₂N₃O₅S 517.15, found 518.3 (MH⁺).

Example 11.28 Preparation of4-(6-{2-Fluoro-4-[(2-isopropoxy-ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound C101)

Compound C101 was obtained in a similar manner as described in Example11.36 as a solid (30 mg, 20%). ¹H NMR (DMSO-d₆, 400 MHz) δ 1.08 (d, 6H),1.21 (d, 6H), 1.62-1.73 (m, 2H), 1.92-2.01 (m, 2H), 2.16 (s, 3H), 3.21(q, 2H), 3.31-3.41 (m, 4H), 3.48 (s, 2H), 3.50-3.60 (m, 1H), 3.61-3.71(m, 2H), 4.80 (h, 1H), 5.33 (h, 1H), 7.13 (d, 1H), 7.22-7.30 (m, 2H),8.17 (t, 1H), 8.26 (s, 1H). Exact mass calculated for C₂₇H₃₇FN₄O₆532.60, found 533.4 (MH⁺).

Example 11.29 Preparation of4-{6-[2-Fluoro-4-(2-isopropoxy-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C113)

Compound C113 was obtained in a similar manner as described in Example11.36 as a solid (25 mg, 83%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.03 (d, 6H),1.12 (d, 6H), 1.62-1.65 (m, 2H), 1.86-1.91 (m, 2H), 2.07 (s, 3H),3.25-3.31 (m, 2H), 3.38-3.44 (m, 2H), 3.48-3.53 (m, 3H), 3.60-3.68 (m,2H), 4.74-4.76 (m, 1H), 5.24-5.27 (m, 1H), 7.21 (t, 1H), 4.56-7.59 (m,2H), 8.00 (s, 1H), 8.43 (t, 1H). Exact mass calculated for C₂₆H₃₅FN₄O₆518.2, found 519.5 (MH⁺).

Example 11.30 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-1-one(Compound C115)

Compound C115 was prepared in a similar manner as described in Example11.21 and was obtained as a white powder (27.1 mg, 60%). Exact masscalculated for C₂₁H₂₆FN₃O₅S 451.2, found 452.2 (MH⁺).

Example 11.31 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-1-one(Compound C116)

Compound C116 was prepared in a similar manner as described in Example11.21 and was obtained as a white powder (29.9 mg, 64%). Exact masscalculated for C₂₂H₂₈FN₃O₅S 465.2, found 466.4 (MH⁺).

Example 11.32 Preparation of4-[6-(2,4-Difluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C117)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.0 g, 3.19 mmol), 2,4-difluoro-phenol (585 mg, 4.5mmol), and potassium carbonate (882 mg, 6.38 mmol) in DMF (11 mL) washeated under microwave irradiation for 80 min at 150° C. The crudemixture was concentrated in vacuo and purified by HPLC to provideCompound C117 as a beige solid (890 mg, 69%). ¹H NMR (CDCl₃, 400 MHz) δ1.19 (d, 6H), 1.66-1.76 (m, 2H), 1.86-1.95 (m, 2H), 2.11 (s, 3H),3.30-3.40 (m, 2H), 3.63-3.73 (m, 2H), 4.86 (m, 1H), 5.26 (m, 1H),6.80-6.91 (m, 2H), 7.09 (q, 1H), 7.19 (s, 1H). Exact mass calculated forC₂₀H₂₃F₂N₃O₄ 407.41, found 408.3 (MH⁺).

Example 11.33 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one(Compound C119)

Compound C119 was obtained in a similar manner as described in Example11.21 as a white powder (28.5 mg, 61%). Exact mass calculated forC₂₂H₂₈FN₃O₅S 465.2, found 466.4 (MH⁺).

Example 11.34 Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-1-one(Compound C120)

Compound C120 was obtained in a similar manner as described in Example11.21 as an oil (33.3 mg, 69%). Exact mass calculated for C₂₃H₃₀FN₃O₅S479.2, found LCMS (ESI) m/z 480.4 (MH⁺).

Example 11.35 Preparation of4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-butyricacid (Compound C51)

Compound C51 was obtained in a similar manner as described in Example11.21 as a white powder (11.9 mg, 25%). Exact mass calculated forC₂₁H₂₄FN₃O₇S 481.1, found LCMS (ESI) m/z 482.2 (Mft).

Example 11.36 Preparation of4-{6-[2-Fluoro-4-(2-methoxy-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C122)

A mixture of4-[6-(4-Carboxy-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (150 mg, 0.346 mmol), 2-Methoxy-ethylamine (31 mg,0.41 mmol), HATU (157 mg, 0.42 mmol) and triethyl amine (70 mg, 0.7mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixturewas purified through HPLC to provide Compound C122 (115 mg, 68%) as asolid. ¹H NMR (MeOH-d₄, 400 MHz) δ 1.22 (d, J=6.82 Hz, 6H), 1.71-1.74(m, 2H), 1.97-2.00 (m, 2H), 2.16 (s, 3H), 3.34 (s, 3H), 3.35-3.39 (m,2H), 3.53 (s, 4H), 3.71-3.74 (m, 2H), 4.81-4.84 (m, 1H), 5.33-5.36 (m,1H), 7.30 (t, J=8.1 Hz, 1H), 7.66-7.69 (m, 2H), 8.09 (s, 1H). Exact masscalculated for C₂₄H₃₁FN₄O₆490.2, found 491.4 (MH⁺).

Example 11.37 Preparation of4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C127) Step 1: Preparation of4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.0098 g, 3.2 mmol), potassium carbonate (889.5 mg,6.43 mmol), and 4-bromo-2-fluorophenol (458 μl, 4.18 mmol) in 15 mL DMFwas heated in microwave for 1 hour at 150° C. The mixture was purifiedby HPLC to give4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester as a tanned solid as the TFA salt (Compound C130,741 mg, 39%). Exact mass calculated for C₂₀H₂₃BrFN₃O₄ 467.09, found468.3 (MH⁺).

Step 2:4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C127)

A mixture of4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (741 mg, 1.27 mmol), sodium methane sulfinate(288.4 mg, 2.82 mmol), and N,N′-dimethyl-ethylene diamine (28 mg, 0.317mmol) and copper (I) trifluoromethane sulfonate benzene complex (95.6mg, 0.190 mmol) in 10 mL DMSO was heated in microwave for 30 min at 160°C. The mixture was purified by HPLC to give Compound C127 as a whitesolid (TFA salt, 327.1 mg, 44%). ¹H NMR (CD₃CN-d₃, 400 MHz) δ 1.21-1.23(d, J=6.32 Hz, 6H), 1.69-1.77 (m, 2H), 1.93-1.95 (m, 2H), 2.184 (s, 3H),3.125 (s, 3H), 3.359-3.441 (m, 2H), 3.650-3.734 (m, 2H), 4.84 (hept,J=6.32 Hz, 1H), 5.313-5.380 (m, 1H), 7.470-7.526 (m, 1H), 7.781-7.846(m, 2H) 8.158 (s, 1H). Exact mass calculated for C₂₁H₂₆FN₃O₆S 467.15,found 468.4 (MH⁺).

Example 11.38 Preparation of4-{6-[2-Fluoro-4-(methoxy-methyl-carbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl este (Compound C132) Compound C132 was obtained in asimilar manner as described in Example 11.36 as an oil (40 mg, 85%). ¹HNMR (CDCl₃, 400 MHz) δ 1.26 (d, J=6.32 Hz, 6H), 1.75-1.83 (m, 2H),1.96-2.02 (m, 2H), 2.18 (s, 3H), 3.38 (s, 3H), 3.39-3.46 (m, 2H), 3.60(s, 3H), 3.71-3.77 (m, 2H), 4.93 (hept, J=6.32 Hz, 1H), 5.31-5.36 (m,1H), 7.21-7.26 (m, 1H), 7.58-7.62 (m, 2H), 8.20 (s, 1H). Exact masscalculated for C₂₃H₂₉FN₄O₆ 476.2, found 477.3 (MH⁺). Example 11.39Preparation of1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-1-one(Compound C133)

Compound C132 was prepared in a similar manner as described in Example11.21 and was obtained as a white powder (30.5 mg, 65%). Exact masscalculated for C₂₁H₂₆FN₃O₆S 467.1, found LCMS (ESI) m/z 468.2 (MH⁺).

Example 11.40 Preparation of4-[6-(4-Cyano-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C134)

A mixture of4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C130, 1.14 g, 2.4 mmol), zinc cyanide(290 mg, 2.42 mmol), and tetrakistriphenylphosphinepalladium (0) (281mg, 0.24 mmol) in DMF (15 mL) was purged with Argon and heated undermicrowave irradiation at 180° C. for 8 min. The crude mixture waspurified by HPLC to provide Compound C134 as a solid (TFA salt, 318 mg,27%). ¹H NMR (CDCl₃, 400 MHz) δ 1.27-1.28 (d, J=6.32 Hz, 6H), 1.81-1.84(m, 2H), 1.99-2.02 (m, 2H), 2.20 (s, 3H), 3.43-3.49 (m, 2H), 3.75-3.77(m, 2H), 4.94-4.97 (m, J=6.32 Hz, 1H), 5.35-5.36 (m, J=3.79 Hz, 1H),7.33-7.37 (m, 1H), 7.49-7.54 (m, 2H), 8.21 (s, 1H). Exact masscalculated for C₂₁H₂₃PN₄O₄ 414.17, found 415.4 (MH⁺).

Example 11.41 Preparation of4-[5-(5-Aminomethyl-4,5-dihydro-oxazol-2-yl)-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C135)

In a 100 mL round-bottomed flask fitted with a condenser and N₂ inletwas placed a stir bar,4-[5-cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (1 g, 2 mmol), ZnCl₂ (30 mg, 0.2 mmol),1,3-diamino-propan-2-ol (180 mg, 2 mmol), and chlorobenzene (20 mL). Thereaction mixture was heated under reflux overnight. After it was cooleddown to room temperature, the reaction was quenched with H₂O. Theresulting suspension was extracted with EtOAc. The organic extracts wasdried and concentrated under vacuum. The crude residue was purified bypreparative HPLC to give Compound C135. ¹H NMR (CDCl₃, 400 MHz) δ 1.25(d, 6H), 1.73 (m, 2H), 1.94 (m, 2H), 2.98 (s, 3H), 3.31 (m, 2H), 3.46(m, 2H), 3.69 (m, 4H), 4.48 (m, 1H), 4.83 (m, 1H), 5.36 (m, 1H), 7.40(d, 1H), 7.49 (d, 1H), 8.36 (t, 1H), 8.44 (s, 1H), 9.52 (m, 2H). Exactmass calculated for C₂₄H₃₁FN₆O₆S 550.20, found 551.3 (MH⁺).

Example 11.42 Preparation of4-{6-[6-(2-Methoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C136)

Using a similar procedure as described in Example 11.4 for thepreparation of Compound C10, Compound C136 was obtained as a tannedsolid (TFA salt, 167.8 mg, 65%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.48-1.49(d, 6H), 1.95-2.02 (m, 2H), 2.21-2.28 (m, 2H), 2.43 (s, 3H), 2.58 (s,3H), 3.61-3.67 (m, 5H), 3.85-3.89 (m, 4H), 3.95-4.03 (m, 2H), 5.10-5.13(m, 1H), 7.20-7.22 (d, 1H), 7.98-8.00 (d, 1H), 7.98-8.00 (d, 1H), 8.40(s, 1H). Exact mass calculated for C₂₃H₃₃N₅O₅ 459.25, found 460.3(MH⁺).¹

Example 11.43 Preparation of4-{6-[6-(3-Methanesulfonyl-pyrrolidin-1-yl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C137)

Using a similar procedure as described in Example 11.4 for thepreparation of Compound C10, Compound C137 was obtained as an oil (TFAsalt, 54.4 mg, 58%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.22-1.23 (d, 6H),1.69-1.77 (m, 2H), 1.95-2.02 (m, 2H), 2.18 (s, 3H), 2.38 (s, 3H),2.52-2.70 (m, 2H), 3.07 (s, 3H), 3.32-3.42 (m, 2H), 3.71-4.19 (m, 8H),5.35-5.38 (m, 1H), 6.97-6.99 (d, 1H), 7.80-7.83 (d, 1H), 8.12 (s, 1H).Exact mass calculated for C₂₅H₃₅N₅O₆S 533.23, found 534.5 (MH⁺).

Example 11.44 Preparation of4-[6-(6-Benzylamino-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C138)

Using a similar procedure as described in Example 11.4 for thepreparation of Compound C10, Compound C138 was obtained as an oil (TFAsalt, 80.8 mg, 61%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.07-1.10 (d, 6H),1.68-1.77 (m, 2H), 1.93-1.91 (m, 2H), 2.17 (s, 3H), 2.34 (s, 3H),3.31-3.41 (m, 2H), 3.69-3.78 (m, 2H), 3.94 (s, 1H), 4.61 (s, 2H),5.31-5.36 (m, 1H), 6.89-6.91 (d, 1H), 7.30-7.39 (m, 5H), 7.73-7.75 (d,1H), 8.13 (s, 1H). Exact mass calculated for C₂₇H₃₃N₅O₄ 491.25, found492.5 (MH⁺).

Example 11.45 Preparation of2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone(Compound C61)

Compound C61 was prepared in a similar manner as described in Example11.7. ¹H NMR (CDCl₃, 400 MHz) δ 2.18 (s, 3H), 2.24 (m, 1H), 2.29 (m,1H), 2.57 (m, 2H), 3.11 (s, 3H), 3.52 (m, 2H), 3.77 (m, 2H), 4.98 (s,2H), 5.60 (m, 1H), 7.45 (t, 1H), 7.60 (m, 1H), 7.82 (m, 2H), 7.91 (m,1H), 8.10 (m, 1H), 8.23 (m, 1H), 8.67 (m, 1H). Exact mass calculated forC₂₄H₂₅FN₄O₅S 500.15, found 501.1 (MH⁺).

Example 11.46 Preparation of4-{6-[2-Fluoro-4-(2-isopropoxy-ethylamino)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C140)

Compound C140 was obtained in a similar manner as described in Example9.71 (Compound A95) as a orange oil (54 mg, 55%). ¹H NMR (CDCl₃, 400MHz) δ 1.19 (d, J=6.1 Hz, 6H), 1.27 (d, J=6.1 Hz, 6H), 1.79-1.83 (m,2H), 1.97-2.02 (m, 2H), 2.20 (s, 3H), 3.41-3.48 (m, 2H), 3.65-3.69 (m,3H), 3.73-3.78 (m, 2H), 4.95 (sept, J=6.3 Hz, 1H), 5.33-5.36 (m, 1H),6.91-6.97 (m, 2H), 7.18 (t, J=8.3 Hz, 1H), 8.23 (s, 1H). Exact masscalculated for C₂₅H₃₅FN₄O₅ 490.3, found 491.4 (MH⁺).

Example 11.47 Preparation of4-(6-{2-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound C141)

Compound C141 was obtained in a similar manner as described in Example9.71 as a tan solid (62 mg, 63%). ¹H NMR (CDCl₃, 400 MHz) δ 1.26 (d,J=6.3 Hz, 6H), 1.61-1.70 (m, 1H), 1.76-1.84 (m, 2H), 1.94-1.99 (m, 4H),2.04-2.11 (m, 1H), 2.18 (s, 3H), 3.11 (dd, J=12.4 Hz, 8.3 Hz 1H), 3.29(dd, J=12.4 Hz, 3.8 Hz, 1H), 3.41-3.47 (m, 2H), 3.72-3.79 (m, 2H),3.80-3.84 (m, 2H), 3.88-3.94 (m, 2H), 4.17 (qd, J=8.5 Hz, 3.5 Hz, 1H),4.94 (sept, J=6.3 Hz, 1H), 5.30-5.36 (m, 1H), 6.64 (dd, J=12.1 Hz, 2.5Hz, 1H), 6.66 (dd, J=14.9 Hz, 2.5 Hz, 1H), 7.05 (t, J=8.3 Hz, 1H), 8.23(s, 1H). Exact mass calculated for C₂₅H₃₃FN₄O₅ 488.2, found 489.4 (MH⁺).

Example 11.48 Preparation of4-(6-{6-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound C142)

Using a similar procedure as described in Example 11.4 for thepreparation of Compound C10, Compound C142 was obtained as an oil (TFAsalt, 54.1 mg, 50%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.00-1.02 (d, 6H),1.70-1.77 (m, 2H), 1.95-2.02 (m, 2H), 2.17 (s, 3H), 2.33 (s, 3H), 3.00(s, 3H), 3.19 (s, 3H), 3.34-3.41 (m, 2H), 3.49-3.53 (t, 2H), 3.70-3.76(m, 2H), 3.94 (s, 1H), 4.09-4.12 (t, 2H), 5.33-5.36 (m, 1H), 6.84-6.86(d, 1H), 7.53-7.55 (d, 1H), 8.10 (s, 1H). Exact mass calculated forC₂₄H₃₅N₅O₆S 521.23, found 522.5 (MH⁺).

Example 11.49 Preparation of4-[6-(2-Fluoro-4-hydroxycarbamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C143)

Compound C143 was obtained in a similar manner as described in Example11.36 as an oil (66 mg, 80%). Exact mass calculated forC₂₁H₂₅FN₄O₆448.2, found 449.3 (MH⁺).

Example 11.50 Preparation of4-{6-[2-Fluoro-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C144)

Compound C144 was obtained in a similar manner as described in Example11.36 as a solid (30 mg, 58%). ¹H NMR (CDCl₃, 400 MHz) δ 1.13 (d, 6H),1.65-1.69 (m, 2H), 1.83-1.87 (m, 2H), 2.06 (s, 3H), 2.13-2.22 (m, 4H),2.90-2.93 (m, 2H), 3.28-3.37 (m, 4H), 3.58-3.65 (m, 2H), 3.70-3.79 (m,4H), 4.81 (hept, 1H), 5.18-5.23 (m, 1H), 7.15-7.18 (m, 1H), 7.59-7.65(m, 2H), 7.82 (t, 1H), 8.05 (s, 1H), 10.0 (s, 1H). Exact mass calculatedfor C₂₇H₃₆FN₅O₅ 529.3, found 530.3 (MH⁺).

Example 11.51 Preparation of4-{6-[2-Fluoro-4-(4-isopropyl-piperazine-1-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C145)

Compound C145 was obtained in a similar manner as described in Example11.36 as a solid (29 mg, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 1.17 (d, 6H),1.33 (d, 6H), 1.62-1.77 (m, 2H), 1.85-1.95 (m, 6H), 2.10 (s, 3H),2.70-2.80 (m, 1H), 3.31-3.51 (m, 6H), 3.58-3.69 (m, 2H), 4.84 (hept,1H), 5.23-5.28 (m, 1H), 7.21-7.26 (m, 3H), 8.09 (s, 1H), 10.2 (s, 1H).Exact mass calculated for C₂₈H₃₈FN₅O₅ 543.3, found 544.5 (MH⁺).

Example 11.52 Preparation of4-{6-[2-Fluoro-4-(2-morpholin-4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C146) Step 1: Preparation of(3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester

To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (20 g, 117.5mmol) in MeOH (150 mL), was H₂SO₄ (3 drops) added. The reaction mixturewas heated to reflux and maintained for 2 hours. The reaction was cooledto room temperature and 5 g of NaHCO₃ was added portionwise. Thereaction was concentrated under vacuum and dissolved in ether (200 mL).The ether layer was washed with sat. NaHCO₃. The ether layer was driedover MgSO₄, and concentrated under vacuum to afford the desired compound(19.9 g, 92%) as an oil. The crude compound was used for the next stepwithout further purification. ¹H NMR (400 Mz, DMSO-d₆) δ 9.92 (s, 1H),7.01-7.20 (m, 2H), 3.62 (s, 2H), 3.61 (s, 3H). LCMS 185.1 [MH⁺].

Step 2: Preparation of (4-benzyloxy-3-fluoro-phenyl)-acetic acid methylester

To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester(15 g, 54.3 mmol) and benzyl bromide (9.28 g, 54.3 mmol) in DMF (50 mL),was K₂CO₃ (7.24 g, 54.3 mmol) added at an ambient temperature. Thereaction mixture was heated to 60° C. and maintained for 2 hours. Thereaction was cooled to room temperature and poured into H₂O (150 mL).The organic compound was extracted with ether (150 mL) and washed withsat NaHCO₃ (100 mL). The ether layer was dried over MgSO₄, andconcentrated under vacuum to afford the desired compound (12.9 g, 87.9%)as a white crystal. The crude compound was used for the next stepwithout further purification. ¹H NMR (400 Mz, DMSO-d₆) δ 7.41-7.49 (m,5H), 7.15-7.23 (m, 2H), 7.02-7.04 (m, 1H), 5.19 (s, 2H), 3.65 (s, 2H),3.63 (s, 3H). LCMS 273.4 [MH⁺].

Step 3: Preparation of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol

To a solution of (4-benzyloxy-3-fluoro-phenyl)-acetic acid methyl ester(7.1 g, 25.7 mmol) in ether (150 mL), was LAH (1.07 g, 28.3 mmol) addedportionwise at 0° C. The reaction mixture stirred for 2 hours at thesame temperature. The reaction was quenched with H₂O (5 mL) at 0° C. Thesolid material was filtrated off and washed with ether (50 mL). Theether was dried over MgSO₄ and concentrated under vacuum to afford thedesired compound (5.2 g, 82%) as a white solid. The crude compound wasused for the next step without further purification. ¹H NMR (400 Mz,DMSO-d₆) δ 7.34-7.48 (m, 5H), 7.09-7.17 (m, 2H), 6.96-6.98 (m, 1H), 5.17(s, 2H), 4.66 (s, 1H), 3.60 (b, 2H), 2.68 (m, 2H). LCMS 246.3 [MH⁺].

Step 4: Preparation of 1-benzyloxy-4-(2-bromo-ethyl)-2-fluoro-benzene

To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (1.0 g, 4.0mmol) and CBr₄ (1.5 g, 4.5 mmol) in CH₂Cl₂ (10 mL), was PPh₃ (1.2 g, 4.5mmol) added portionwise at 0° C. The reaction mixture stirred for 2hours at the same temperature. The reaction was concentrated undervacuum and the residue was stirred in ether (10 mmol). The solid, mainlytriphenylphosphine oxide, was filtrated off and the filtrate wasconcentrated under vacuum. The residue was purified over SiO₂ to affordthe desired compound (1.15 g, 93.5%) as a white crystal. ¹H NMR (400 Mz,DMSO-d₆) δ 7.36-7.49 (m, 5H), 7.17-7.23 (m, 2H), 7.03-7.05 (m, 1H), 5.18(s, 2H), 3.72 (t, 2H), 3.08 (t, 2H). LCMS 273.4 [MH⁺].

Step 5: Preparation of 2-fluoro-4-(2-morpholin-4-yl-ethyl)-phenol

To a solution of 1-benzyloxy-4-(2-bromo-ethyl)-2-fluoro-benzene (1.0 g,3.2 mmol) and morpholine (278 mg, 3.2 mmol) in DMF (5 mL), was K₂CO₃(432 mg, 3.2 mmol) added. The reaction mixture was heated to 60° C. andmaintained for 6 hours. The reaction was cooled to room temperature andpoured into H₂O (50 mL). The organic compound was extracted with ethylacetate (50 mL) and dried over MgSO₄. The ethyl acetate layer wasconcentrated under vacuum and dissolved in methanol (50 mL). Thesolution was treated with Pd/C (20 mg) and stirred under H₂ (latm) for 3hours. The solid material was filtrated off and the filtrate wasconcentrated under vacuum to afford the desired compound (790 mg, 93%)as a white oil. The crude compound was used for the next step withoutfurther purification. ¹H NMR (400 Mz, DMSO-d₆) δ 7.33-7.45 (m, 5H),7.09-7.15 (m, 2H), 6.97-7.01 (m, 1H), 5.13 (s, 2H), 3.56 (m, 4H),2.64-2.68 (m, 2H), 2.44-2.50 (m, 2H), 2.39 (b, 2H). LCMS 310.5 [MH⁺].

Step 6: Preparation of4-{6-[2-Fluoro-4-(2-morpholin-4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C146)

To a solution of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (270 mg, 0.84 mmol) and2-fluoro-4-(2-morpholin-4-yl-ethyl)-phenol (225 mg, 0.84 mmol) in DMF (5mL), was K₂CO₃ (137 mg, 0.84 mmol) added. The reaction mixture wasirradiated under microwave for 1 hour at 150° C. The reaction was cooledto room temperature and poured into H₂O (50 mL) and extracted with ethylacetate (50 mL). The ethyl acetate was dried over MgSO₄, andconcentrated under vacuum and purified over SiO₂ to afford Compound C146(380 mg, 90%) as a white solid. ¹H NMR (400 Mz, DMSO-d₆) δ 8.06 (s, 1H),7.09-7.02 (m, 1H), 6.93-6.91 (m, 2H), 5.12 (m, 1H), 4.61 (m, 1H),3.46-3.37 (m, 6H), 3.18-3.13 (m, 2H), 2.61-2.57 (m, 2H), 2.38-2.26 (m,2H), 2.25 (b, 2H), 1.96 (s, 3H), 1.79-1.74 (m, 2H), 1.49-1.45 (m, 2H),1.03 (d, 6H). LCMS 503.5 [M+1].

Example 11.53 Preparation of4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C147) Step 1: Preparation of1-benzyloxy-2-fluoro-4-(2-methanesulfonyl-ethyl)-benzene

To a solution of 1-benzyloxy-4-(2-bromo-ethyl)-2-fluoro-benzene (1.9 g,6.25 mmol) in MeOH (150 mL), was NaSCH₃ (439 mg, 6.25 mmol) added at 0°C. The reaction mixture was warmed to room temperature. After stirringfor 5 hours, the reaction was concentrated under vacuum. The residue wasdissolved in CH₂Cl₂ (10 mL) and mCPBA (2.7 g, 15.6 mmol) was addedportionwise at 0° C. The reaction was warmed to room temperature andstirred for 3 hours. The reaction was dissolved with ether (20 mL) andwashed with sat. NaHCO₃. The ether layer was dried over MgSO₄, andconcentrated under vacuum. The residue was purified over SiO₂ to affordthe desired compound (1.92 g, 89.6%) as a yellowish crystal. ¹H NMR (400Mz, DMSO-d₆) δ 7.49˜7.33 (m, 5H), 7.23˜7.15 (m, 2H), 7.05˜7.03 (m, 1H),5.15 (s, 2H), 3.42˜3.36 (m, 2H), 2.96˜2.93 (m, 2H), 2.94 (s, 3H). LCMS309.5 [MH⁺].

Step 2: Preparation of 2-fluoro-4-(2-methanesulfonyl-ethyl)-phenol

To a solution of 1-benzyloxy-2-fluoro-4-(2-methylsulfonyl-ethyl)-benzene(1.5 g, 4.87 mmol) in MeOH (25 mL) was added Pd/C (50 mg). The reactionwas stirred under H₂ (latm) for 3 hours. The solid material wasfiltrated off and the filtrate was concentrated under vacuum to affordthe desired compound (981 mg, 92.4%) as a yellowish solid. The crudecompound was used for the next step without further purification. ¹H NMR(400 Mz, DMSO-d₆) δ 9.73 (s, 1H), 7.14˜7.11 (m, 1H), 6.94˜6.87 (m, 2H),3.43˜3.37 (m, 2H), 2.98 (s, 3H), 2.95˜2.91 (m, 2H). LCMS 228.2 [MH⁺].

Step 3: Preparation of4-{6-[2-fluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C147)

To a solution of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (270 mg, 0.84 mmol) and2-fluoro-4-(2-2-methylsulfonyl-ethyl)-phenol. (218 mg, 0.84 mmol) in DMF(5 mL), was K₂CO₃ (137 mg, 0.84 mmol) added. The reaction mixture wasirradiated under microwave for 1 hour at 150° C. The reaction was cooledto room temperature and poured into H₂O (50 mL) and extracted with ethylacetate (50 mL). The ethyl acetate was dried over MgSO₄, andconcentrated under vacuum and purified over SiO₂ to afford Compound C147(286 mg, 68%) as a white solid. ¹H NMR (400 Mz, DMSO-d₆) δ 8.25 (s, 1H),7.39˜7.35 (m, 1H), 7.30˜7.26 (m, 1H), 7.21˜7.18 (m, 1H), 5.31 (m, 1H),4.79 (m, 1H), 3.67˜3.65 (m, 2H), 3.64˜3.47 (m, 2H), 3.37˜3.31 (m, 2H),3.08 (m, 2H), 2.97 (s, 3H), 2.15 (s, 3H), 2.00˜1.93 (m, 2H), 1.68˜1.64(m, 2H), 1.23 (d, 6H). LCMS 496.5 [MH⁺].

Example 11.54 Preparation of4-{6-[2-Fluoro-4-(2-hydroxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C148) Step 1: Preparation of4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-fluoro-phenol

To a solution of 2-(4-benzyloxy-3-fluoro-phenyl)-ethanol (9.2 g, 37.4mmol) in CH₂Cl₂ (150 mL) and TBDMS-Cl (5.6 g, 37.4 mmol), was added Et₃N(5.2 mmol, 37.4 mmol) portionwise at 0° C.

The reaction mixture was warmed to room temperature and stirred for 2hours at the same temperature. The reaction was washed with H₂O (150mL). The CH₂Cl₂ was dried over MgSO₄ and concentrated under vacuum. To asolution of the residue in MeOH (100 mL), was Pd/C (150 mg) added. Thereaction was stirred under H₂ (latm) for 5 hours. The solid material wasfiltrated off and the filtrate was concentrated under vacuum to affordthe desired compound (8.9 g, 88.3%) as a grayish solid. The crudecompound was used for the next step without further purification. ¹H NMR(400 Mz, DMSO-d₆) δ 9.53 (s, 1H), 6.99˜6.96 (m, 1H), 6.83˜6.81 (m, 2H),3.70 (t, 2H), 2.63 (t, 2H), 0.83 (s, 9H), 0.01 (s, 6H).

Step 2: Preparation of4-{6-[2-fluoro-4-(2-hydroxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C148)

To a solution of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (270 mg, 0.84 mmol) and4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-fluoro-phenol (279 mg,0.84 mmol) in DMF (5 mL), was K₂CO₃ (137 mg, 0.84 mmol) added. Thereaction mixture was irradiated under microwave for 1 hour at 150° C.The reaction was cooled to room temperature and treated with 1.0 M TBAFin THF (0.9 mL). After stirring for 2 hours, the reaction was pouredinto H₂O (50 mL) and extracted with ethyl acetate (50 mL). The ethylacetate was dried over MgSO₄, and concentrated under vacuum and purifiedover SiO₂ to afford the desired compound (321 mg, 89%) as a white solid.¹H NMR (400 Mz, DMSO-d₆) δ 8.21 (s, 1H), 7.38˜7.37 (m, 1H), 7.29˜7.28(m, 1H), 7.21˜7.17 (m, 1H), 5.30 (m, 1H), 4.75 (m, 1H), 3.67˜3.65 (m,2H), 3.64˜3.41 (m, 2H), 3.33˜3.30 (m, 2H), 3.02 (m, 2H), 2.91 (s, 3H),1.99˜1.93 (m, 2H), 1.66˜1.64 (m, 2H), 1.22 (d, 6H). LCMS 432.6 [MH⁺].

Example 11.55 Preparation of4-[6-(4-Carboxymethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C149)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (1.6 g, 5.32 mmol), (3-fluoro-4-hydroxy-phenyl)-aceticacid (1.8 g, 10.64 mmol), and sodium hydride (638 mg, 26.61 mmol) indimethylacetamide (18 mL) was heated under microwave irradiation for 1hr at 150° C. The reaction was quenched with water and the productextracted in ethyl acetate. The organic layer was concentrated in vacuoand purified by flash chromatography to provide compound C149 as a whitesolid (3.4 g, 48%). ¹H NMR (DMSO-d₆, 400 MHz) δ 1.12 (d, 6H), 1.53-1.63(m, 2H), 1.82-1.92 (m, 2H), 2.07 (s, 3H), 3.22-3.31 (m, 2H), 3.37-3.52(m, 2H), 3.52-3.61 (m, 2H), 4.71 (h, 1H), 5.19-5.28 (h, 1H), 7.06 (d,1H), 7.16-7.23 (m, 2H), 8.17 (s, 1H). Exact mass calculated forC₂₂H₂₆FN₃O₆ 447.46, found 448.3 (MH⁺).

Example 11.56 Preparation of4-[6-(4-Dimethylcarbamoylmethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C150)

A mixture of4-[6-(4-carboxymethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (150 mg, 0.335 mmol) and HATU (178 mg, 0.469 mmol)in DMF (4 mL) was stirred for 30 minutes at room temperature. Then,dimethylamine (235 μL, 0.47 mmol) was added and the reaction was stirredfor 24 hours at room temperature. The reaction was quenched with waterand the product extracted in ethyl acetate. The organic layer wasconcentrated in vacuo and purified by HPLC to provide Compound C150 as awhite solid (40 mg, 25%). ¹H NMR (DMSO-d₆, 400 MHz) δ 1.21 (d, 6H),1.62-1.72 (m, 2H), 1.92-2.01 (m, 2H), 2.16 (s, 3H), 2.87 (s, 3H), 3.06(s, 3H), 3.32-3.41 (m, 2H), 3.61-3.69 (m, 2H), 3.75 (s, 2H), 4.08 (h,1H), 5.33 (h, 1H), 7.08 (d, 1H), 7.23-7.33 (m, 2H), 8.27 (s, 1H). Exactmass calculated for C₂₄H₃₁FN₄O₅ 474.53, found 475.5 (MH⁺).

Example 11.57 Preparation of4-[6-(2-Fluoro-4-sulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C151)

A solution of4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (475 mg, 1.01 mmol) in 5 mL tetrahydrofuran wascooled to −78° C. and n-butyl lithium was added. After stirring for 30minutes at −78° C., sulfur dioxide was bubbled vigorously through thesolution for 10 minutes. Solution was allowed to warm to roomtemperature and was concentrated on a rotary evaporator. Residue wasdissolved in 2 mL tetrahydrofuran and hexane was added until a whitesolid precipitated. Solid was filtered and dried under high vacuum(white solid, 265 mg). White solid was dissolved in 15 mL methylenechloride and sulfuryl chloride (100 μl, 1.2 mmol) was added. Afterstirring for 10 minutes at room temperature, mixture was concentratedand residue was dried under high vacuum. Residue was dissolved in 1 mLdioxane, cooled in an ice bath, and 5 mL ammonium hydroxide (28-30% NH₃)was added. After stirring for 5 minutes, mixture was concentrated andpurified by HPLC to give Compound C151 as a white solid (46.7 mg, 10%).¹H NMR (CDCl₃, 400 MHz) δ 1.26-1.27 (d, J=6.3 Hz, 6H), 1.76-1.84 (m,2H), 1.97-2.02 (m, 2H), 2.20 (s, 3H), 3.39-3.46 (m, 2H), 3.74-3.80 (m,2H), 4.89 (s, 2H), 4.89-4.97 (m, 1H), 5.32-5.38 (m, 1H), 7.35-7.39 (m,1H), 7.75-7.79 (m, 2H), 8.19 (s, 1H). Exact mass calculated forC₂₀H₂₅FN₄O₆S 468.15, found 469.4 (MH⁺).

Example 11.58 Preparation of4-[6-(2-Fluoro-4-propionylsulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C152)

To a solution of Compound C151 (33.5 mg, 0.0715 mmol) in 3 mL methylenechloride, triethylamine (30 μl, 0.215 mmol) and propionic anhydride(27.7 μl, 0.215 mmol) were added. After stirring at room temperature for22 hours, solution was concentrated and purified by HPLC. Fractionswhich contained intermediate were concentrated and dried under highvacuum. Residue was dissolved in 2 mL methanol and sodium bicarbonate(6.9 mg, 0.082 mmol) was added. After stirring for 18 hours at roomtemperature, solution was concentrated, dissolved in water/acetonitrileand lyophilized to give Compound C152 as a white solid (34.0 mg, 87%).¹H NMR (DMSO-d₆, 400 MHz) δ 0.85-0.88 (t, J=7.6, 3H), 1.19-1.20 (d,J=6.2, 6H), 1.61-1.69 (m, 2H), 1.92-1.99 (m, 4H), 2.14 (s, 3H),3.33-3.38 (m, 2H), 3.61-3.67 (m, 2H), 4.75-4.81 (m, 1H), 5.29-5.34 (m,1H), 7.32-7.36 (m, 1H), 7.57-7.67 (m, 2H), 8.27 (s, 1H). Exact masscalculated for C₂₃H₂₉FN₄O₇S 524.17, found 525.2 (MH¹).

Example 11.59 Preparation of4-[5-Ethynyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C153)

4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-trimethylsilanylethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (10 mg, 0.018 mmol) was dissolved in THF (0.60 mL)and MeOH (0.30 mL), 1.0 N NaOH (0.036 mL, 0.036 mmol) was added to thereaction mixture, and it was stirred at room temperature for 1 h.Glacial AcOH (0.0041 mL, 0.072 mmol) was then added to give a pH of 5,then the solvents were evaporated in vacuo to give Compound C153 as acrude solid (11 mg) which contained 2 mol eq of AcONa and was of 80%purity (LCMS). LRMS calculated for C₂₂H₂₄FN₃O₆S: 477.14. Found: 478.3(M+H)⁺.

Example 11.60 Preparation of4-{6-[2-Fluoro-4-(2-phosphonooxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C154)

A mixture of4-{6-[2-fluoro-4-(2-hydroxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (100 mg, 0.23 mmol), and phosphorus oxychloride(0.105 mL, 1.15 mmol) in dichloroethane (5 mL) was stirred for 5 hoursat room temperature. Upon evaporation of the organic solvent, thereaction was quenched with water and the product extracted in ethylacetate. The organic layer was concentrated in vacuo and purified byHPLC to provide Compound C154 as a white solid (40 mg, 33%). ¹H NMR(CDCl₃, 400 MHz) δ 1.23 (d, 6H), 1.71-1.81 (m, 2H), 1.90-2.01 (m, 2H),2.15 (s, 3H), 2.89 (t, 2H), 3.34-3.44 (m, 2H), 3.66-3.77 (m, 2H), 4.16(q, 2H), 4.90 (h, 1H), 5.31 (h, 1H), 6.96-7.09 (m, 3H), 7.38-7.58 (sbroad, 2H), 8.18 (s, 1H). Exact mass calculated for C₂₂H₂₉FN₃O₈P 513.45,found 514.3 (MH⁺).

Example 11.61 Preparation of4-(6-{2-Fluoro-4-[2-(2-methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound C156)

Compound C156 was prepared in a similar manner as described in Example11.56 as a solid (200 mg, 77%). Exact mass calculated for C₂₇H₃₅FN₄O₇S578.65, found 579.4 (MH⁺).

Example 11.62 Preparation of4-[6-(4-Carbamoylmethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C157)

Compound C157 was prepared in a similar manner as described in Example11.56 as a solid (80 mg, 40%). Exact mass calculated for C₂₂H₂₇FN₄O₅446.47, found 447.6 (MH⁺).

Example 11.63 Preparation of4-[6-(2-Fluoro-4-{[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-methyl}-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C158)

Compound C158 was prepared in a similar manner as described in Example11.56 as a solid (230 mg, 97%). Exact mass calculated for C₂₇H₃₅FN₄O₆530.59, found 531.5 (MH⁺).

Example 11.64 Preparation of4-(6-[2-Fluoro-4-{2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester (Compound C166)

Compound C166 was prepared in a similar manner as described in Example11.56 as a solid (150 mg, 62%). Exact mass calculated for C₂₇H₃₅FN₄O₅530.59, found 531.3 (MH⁺).

Example 11.65 Preparation of4-{6-[2-Fluoro-4-(2-morpholin-4-yl-2-oxo-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C167)

Compound C167 was prepared in a similar manner as described in Example11.56 as a solid (90 mg, 38%). Exact mass calculated for C₂₆H₃₃FN₄O₆516.56, found 517.4 (MH⁺).

Example 11.66 Preparation of4-{6-[2-Fluoro-4-(2-imidazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C168) General Protocol of Alkylation

A mixture of4-{6-[4-(2-bromo-ethyl)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (30.0 mg, 0.44 mmol) and sodium hydride (11.0 mg,0.44 mmol) in DMF (4 mL) was stirred for 30 minutes at room temperature.Then, imidazole (200 μL, 0.40 mmol) was added and the reaction wasstirred for 2 hours at room temperature. The reaction was quenched withwater and the product extracted in ethyl acetate. The organic layer wasconcentrated in vacuo and purified by HPLC to provide compound C168 as awhite solid (28 mg, 15%). ¹H NMR (CDCl₃, 400 MHz) δ 1.17 (d, 6H),1.66-1.76 (m, 2H), 1.85-1.96 (m, 2H), 2.11 (s, 3H), 3.06-3.14 (m, 2H),3.30-3.37 (m, 2H), 3.62-3.72 (m, 2H), 3.33-3.40 (m, 2H), 4.86 (h, 1H),5.24 (h, 1H), 6.80-6.95 (m, 3H), 7.09 (t, 1H), 7.32 (s, 1H), 8.11 (s,1H), 8.72 (s, 1H). Exact mass calculated for C₂₅H₃₀FN₅O₄ 483.54, found484.4 (MH⁺).

Example 11.67 Preparation of4-{6-[2-Fluoro-4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C169)

Compound C169 was prepared in a similar manner as described in Example11.66 as a solid (105 mg, 54%). Exact mass calculated for C₂₄H₂₉FN₆O₄484.52 found 485.4 (MH⁺).

Example 11.68 Preparation of4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid (R)-tetrahydro-furan-3-yl ester (Compound C177)

To a solution of 1,1′-carbonyldiimidazole (54.8 mg, 0.338 mmol) in 1 mLTHF was added (R)-(+)-3-hydroxytetrahydrofuran (32 μl, 0.38 mmol). Afterstirring for 30 minutes at room temperature, 1 mL triethylamine, 1 mLTHF, and4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine(70 mg, 0.166 mmol) were added. The resulting mixture was stirred at 60°C. for 48 hours and purified by HPLC to give Compound C177 as a whitesolid (35.3 mg, 42%). ¹H NMR (CDCl₃, 400 MHz) δ 1.81-1.88 (m, 2H),1.96-2.09 (m, 3H), 2.12-2.20 (m, 4H), 3.10 (s, 3H), 3.42-3.48 (m, 2H),3.75-3.81 (m, 2H), 3.84-3.97 (m, 4H), 5.27-5.31 (m, 1H), 5.34-5.38 (m,1H), 7.41-7.45 (m, 1H), 7.77-7.82 (m, 2H), 8.20 (s, 1H). Exact masscalculated for C₂₂H₂₆FN₃O₇S 495.15, found 496.3 (MH⁺).

Example 11.69 Preparation of4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid (S)-tetrahydro-furan-3-yl ester (Compound C176)

Compound C176 was prepared in a simper manner as described in Example11.68 as a white solid (40.8 mg, 46%). ¹H NMR (CDCl₃, 400 MHz) δ1.81-1.88 (m, 2H), 1.96-2.09 (m, 3H), 2.12-2.20 (m, 4H), 3.10 (s, 3H),3.42-3.48 (m, 2H), 3.75-3.81 (m, 2H), 3.84-3.97 (m, 4H), 5.27-5.31 (m,1H), 5.34-5.38 (m, 1H), 7.41-7.45 (m, 1H), 7.77-7.82 (m, 2H), 8.20 (s,1H). Exact mass calculated for C₂₂H₂₆FN₃O₇S 495.15, found 496.3 (MH⁺).

Example 11.70 Preparation of4-{6-[2-Fluoro-4-(6-methoxy-pyridin-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C181)

A mixture of4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (184 mg, 0.393 mmol), 6-methoxypyridine-3-boronicacid (67.3, 0.396 mmol), potassium carbonate (164 mg, 1.24 mmol), andtetrakis (triphenylphosphine) palladium (20 mg, 0.046 mmol) in 4 mL THFand 0.4 mL H₂O was heated under microwave irradiation for 1 hour at 120°C. The mixture was purified by HPLC to give Compound C181 as a colorlessoil (TFA salt, 186 mg, 78%). ¹H NMR (CDCl₃, 400 MHz) δ 1.27-1.29 (d,J=6.3 Hz, 6H), 1.80-1.88 (m, 2H), 1.98-2.05 (m, 2H), 2.23 (s, 3H),3.44-3.50 (m, 2H), 3.74-3.80 (m, 2H), 4.12 (s, 3H), 4.93-4.99 (m, 1H),5.34-5.39 (m, 1H), 5.34-5.39 (m, 1H), 7.06-7.08 (m, 1H), 7.33-7.39 (m,3H), 8.07-8.10 (m, 1H), 8.27 (s, 1H), 8.57-8.58 (d, J=2.4 Hz, 1H). Exactmass calculated for C₂₆H₂₉FN₄O₅ 496.21, found 497.4 (MH⁺).

Example 11.71 Preparation of4-[5-Bromo-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C155)

4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (1.02 g, 2.25 mmol) and NBS (601 mg, 3.38 mmol) inacetic acid (10 mL) was stirred at 40° C. for three days. The mixturewas purified through HPLC to provide compound C155 as a solid (685 mg,50%). ¹H NMR (CDCl₃, 400 MHz) δ 1.24 (d, 6H), 1.82-1.86 (m, 2H),1.94-1.98 (m, 2H), 3.08 (s, 3H), 3.46-3.52 (m, 2H), 3.68-3.74 (m, 2H),4.92 (hept, 1H), 5.38-5.42 (m, 1H), 7.42-7.46 (m, 1H), 7.77-7.81 (m,2H), 8.18 (s, 1H). Exact mass calculated for C₂₀H₂₃FBrN₃O₆S 531.1, found532.4/534.4 (MH⁺).

Example 11.72 Preparation of4-[6-(4-Methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C179)

Compound C179 was prepared in a similar manner as described in Example11.15 as a solid (60 mg, 67%). ¹H NMR (CDCl₃, 400 MHz) δ 1.26 (d, 6H),1.77-1.85 (m, 2H), 1.98-2.03 (m, 2H), 2.18 (s, 3H), 3.08 (s, 3H),3.41-3.47 (m, 2H), 3.74-3.80 (m, 2H), 4.95 (hept, 1H), 5.35-5.39 (m,1H), 7.30-7.33 (m, 2H), 7.98-8.01 (m, 2H), 8.28 (s, 1H). Exact masscalculated for C₂₁H₂₇N₃O₆S 449.2, found 450.3 (MH⁺).

Example 11.73 Preparation of4-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C178)

Compound C178 was prepared in a similar manner as described in Example11.15 as a solid (66 mg, 69%). ¹H NMR (CDCl₃, 400 MHz) δ 1.11 (t, 3H),1.20 (d, 6H), 1.59-1.66 (m, 2H), 1.90-1.95 (m, 2H), 2.08 (s, 3H), 3.19(quart, 2H), 3.30-3.35 (m, 2H), 3.60-3.67 (m, 2H), 4.78 (hept, 1H),5.24-5.30 (m, 1H), 7.10 (d, 1H), 7.48 (dd, 1H), 7.99 (s, 2H), 8.27 (s,1H), 8.33 (d, 1H). Exact mass calculated for C₂₂H₃₀N₄O₆S 478.2, found479.2 (MH⁺).

Example 11.74 Preparation of4-[5-Methyl-6-(4-sulfo-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C185)

Compound C185 was prepared in a similar manner as described in Example11.15 as a solid (21 mg, 23%). ¹H NMR (CDCl₃, 400 MHz) δ 1.20 (d, 6H),1.63-1.67 (m, 2H), 1.91-1.97 (m, 2H), 2.12 (s, 3H), 3.32-3.36 (m, 2H),3.62-3.67 (m, 2H), 4.78 (quint, 1H), 5.30-5.32 (m, 1H), 7.06-7.09 (m,2H), 7.61-7.64 (m, 2H), 8.24 (s, 1H). Exact mass calculated forC₂₀H₂₅N₃O₇S 451.1, found 452.3 (MH⁺).

Example 11.75 Preparation of4-{6-[2-Fluoro-4-(2-isopropoxy-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C184)

Mixture of4-(6-Chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (147 mg, 0.47 mmole),2-fluoro-4-(2-isopropoxy-ethoxy)-phenol (0.47 mmole, 1 eq) and K₂CO₃(0.75 mmole, 1.5 eq) in 2 mL DMSO was heated under microwave irradiationat 150° C. for 40 minutes. Mixture was purified by HPLC to give compoundC184 as a yellow oil (273 mg, 96%). ¹H NMR (DMSO-d₆, 400 MHz) δ 1.23 (d,6H), 1.27 (d, 6H), 1.79-1.86 (m, 2H), 1.97-2.04 (m, 1H), 2.20 (s, 3H),3.43-3.50 (m, 2H), 3.73-3.79 (m, 3H), 3.82 (t, 2H), 4.09 (t, 2H), 4.95(sep, 1H), 5.33-5.36 (m, 1H), 6.70-6.78 (m, 2H), 7.08 (t, 1H), 8.27 (s,1H). Exact mass calculated for C₂₅H₃₄FN₃O₆ 491.2, found 492.4 (MH⁺).

Example 11.76 Preparation of3-tert-Butoxy-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-propan-1-one(Compound C161)

Mixture of4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine(76 mg, 0.2 mmole), 3-tert-butoxy-propionic acid (0.26 mmole, 1.3 eq),HATU (0.26 mmole, 1.3 eq), and triethylamine (0.4 mmole, 2 eq) in 2 mLDMF was stirred at room temp for 2 hours. Mixture was purified by HPLCto give compound C161 as a white solid (88 mg, 86%). ¹H NMR (CDCl₃, 400MHz) δ 1.20 (s, 9H), 1.91-1.96 (m, 2H), 2.02-2.10 (m, 2H), 2.22 (s, 3H),2.72 (t, 2H), 3.11 (s, 3H), 3.62-3.64 (m, 2H), 3.72 (t, 2H), 3.86-3.91(m, 2H), 5.41-5.46 (m, 1H), 7.44 (t, 1H), 7.78-7.82 (m, 2H), 8.23 (s,1H). Exact mass calculated for C₂₄H₃₂FN₃O₆S 509.2, found 510.6 (MH⁺).

Example 11.77 Preparation of2-Ethoxy-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone(Compound C163)

Mixture of4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine(76 mg, 0.2 mmole), 2-ethoxyacetic acid (0.26 mmole, 1.3 eq), HATU (0.26mmole, 1.3 eq), and TEA (0.4 mmole, 2 eq) in 2 mL THF was heated undermicrowave irradiation at 120° C. for 30 minutes. Mixture was purified byHPLC to give compound C163 as a white solid (55 mg, 59%). ¹H NMR (CDCl₃,400 MHz) δ 1.25 (t, 3H), 1.86-1.90 (m, 2H), 2.01-2.09 (m, 2H), 2.22 (s,3H), 3.10 (s, 3H), 3.51-3.69 (m, 2H), 3.59 (q, 2H), 3.76-3.87 (m, 2H),4.21 (s, 2H), 5.41-5.44 (m, 1H), 7.43 (t, 1H), 7.78-7.82 (m, 2H), 8.21(s, 1H). Exact mass calculated for C₂₁H₂₆FN₃O₆S 467.2, found 468.5(MH⁺).

Example 11.78 Preparation of{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-(tetrahydro-furan-2-yl)-methanone(Compound C164)

Mixture of4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine(76 mg, 0.2 mmole), tetrahydro-furan-2-carboxylic acid (0.26 mmole, 1.3eq), HATU (0.26 mmole, 1.3 eq), and TEA (0.4 mmole, 2 eq) in 2 mL THFwas heated under microwave irradiation at 120° C. for 30 minutes.Mixture was purified by HPLC to give compound C164 as a yellow solid (78mg, 81%). ¹H NMR (CDCl₃, 400 MHz) δ 1.85-2.17 (m, 8H), 2.21 (s, 3H),3.10 (s, 3H), 3.75-3.80 (m, 2H), 3.86-3.91 (m, 2H), 3.96-4.01 (m, 2H),4.68 (t, 1H), 5.40-5.45 (m, 1H), 7.44 (t, 1H), 7.78-7.82 (m, 2H), 8.21(s, 1H). Exact mass calculated for C₂₂H₂₆FN₃O₆S 479.2, found 480.3(MH⁺).

Example 11.79 Preparation of(S)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one(Compound C165)

Compound C165 was obtained in a similar manner as described in Example11.78 as a yellow solid (7 mg, 7%). Exact mass calculated forC₂₃H₃₁FN₄O₅S 494.2, found 495.5 (MH⁺).

Example 11.80 Preparation of(S)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-hydroxy-butan-1-one(Compound C171)

Compound C171 was obtained in a similar manner as described in Example11.78 as a white solid (31 mg, 33%). Exact mass calculated forC₂₁H₂₆FN₃O₆S 467.2, found 468.6 (MH⁺).

Example 11.81 Preparation of(R)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one(Compound C170)

Compound C170 was obtained in a similar manner as described in Example11.78 as a yellow solid (16 mg, 16%). Exact mass calculated forC₂₃H₃₁FN₄O₅S 494.2, found 495.5 (MH⁺).

Example 11.82 Preparation of(R)—N-(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-acetamide(Compound C172)

Compound C172 was obtained in a similar manner as described in Example11.78 as a white solid (83 mg, 80%). ¹H NMR (CD₃OD, 400 MHz) δ 0.95-0.99(m, 6H), 1.78-1.91 (m, 2H), 2.00 (s, 3H), 2.04-2.05 (m, 2H), 2.23 (d,3H), 3.19 (s, 3H), 3.58-3.64 (m, 2H), 3.77 (m, 2H), 4.02 (m, 2H), 4.70(d, 1H), 5.45-5.47 (m, 1H), 7.54 (t, 1H), 7.84-7.88 (m, 2H), 8.16 (s,1H). Exact mass calculated for C₂₄H₃₁FN₄O₆S 522.2, found 523.5 (MH⁺).

Example 11.83 Preparation of(S)—N-(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-acetamide(Compound C173)

Compound C173 was obtained in a similar manner as described in Example11.78 as a white solid (89 mg, 80%). ¹H NMR (CD₃OD, 400 MHz) δ 0.96-0.99(m, 6H), 1.77-1.82 (m, 2H), 2.00 (s, 3H), 2.04-2.10 (m, 2H), 2.23 (d,3H), 3.19 (s, 3H), 3.75-3.77 (m, 2H), 3.86-3.88 (m, 2H), 4.02 (m, 2H),4.70 (d, 1H), 5.45-5.47 (m, 1H), 7.55 (t, 1H), 7.85-7.89 (m, 2H), 8.17(s, 1H). Exact mass calculated for C₂₄H₃₁FN₄O₆S 522.2, found 523.5(MH⁺).

Example 11.84 Preparation of(R)—N-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide(Compound C174)

Compound C174 was obtained in a similar manner as described in Example11.78 as a white solid (84 mg, 85%). ¹H NMR (CD₃OD, 400 MHz) δ 1.32 (d,3H), 1.79-1.91 (m, 2H), 1.98 (s, 3H), 2.04-2.10 (m, 2H), 2.23 (d, 3H),3.20 (s, 3H), 3.75-3.99 (m, 2H), 3.86-3.88 (m, 1H), 4.02 (m, 2H),5.46-5.48 (m, 1H), 7.55 (t, 1H), 7.85-7.89 (m, 2H), 8.17 (s, 1H). Exactmass calculated for C₂₂H₂₇FN₄O₆S 494.2, found 495.5 (MH⁺).

Example 11.85 Preparation of(S)—N-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide(Compound C175)

Compound C175 was obtained in a similar manner as described in Example11.78 as a white solid (81 mg, 82%). ¹H NMR (CD₃OD, 400 MHz) δ 1.32 (d,3H), 1.82-1.99 (m, 2H), 2.01 (s, 3H), 2.05-2.15 (m, 2H), 2.24 (d, 3H),3.20 (s, 3H), 3.46-3.55 (m, 2H), 3.74-3.81 (m, 1H), 3.92-4.02 (m, 2H),5.45-5.48 (m, 1H), 7.55 (t, 1H), 7.85-7.90 (m, 2H), 8.17 (s, 1H). Exactmass calculated for C₂₂H₂₇FN₄O₆S 494.2, found 495.5 (MH⁺).

Example 11.86 Preparation of3-Amino-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-1-one(Compound C182)

Compound C182 was obtained in a similar manner as described in Example11.78 as a white solid (3 mg, 3%). Exact mass calculated forC₂₃H₃₁FN₄O₅S 494.2, found 495.5 (MH⁺).

Example 11.87 Preparation of(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-carbamicacid tert-butyl ester (Compound C180)

Compound C180 was obtained in a similar manner as described in Example11.78 as a yellow solid (143 mg, 88%). Exact mass calculated forC₂₇H₃₇FN₄O₇S 580.2, found 581.4 (MH⁺).

Example 11.88 Preparation of2-Amino-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one(Compound C183)

Mixture of compound C180 (68 mg, 0.12 mmole) in 4M HCl in Dioxane (1.5mL) and dioxane (2 mL) was stirred at room temperature for 40 minutes.Mixture was purified by HPLC to give Compound C183 as a white solid (50mg, 86%). ¹H NMR (CD₃OD, 400 MHz) δ 1.04 (d, 3H), 1.13 (d, 3H),1.87-1.92 (m, 2H), 2.04-2.14 (m, 3H), 2.24 (d, NH₂), 2.82 (s, 3H), 3.20(s, 3H), 3.52-3.65 (m, 2H), 3.81-3.83 (m, 2H), 4.36 (m, 1H), 5.49-5.51(m, 1H), 7.55 (t, 1H), 7.86-7.90 (m, 2H), 8.18 (s, 1H). Exact masscalculated for C₂₂H₂₉FN₄O₅S 480.2, found 481.3 (MH⁺).

Example 11.89 Preparation of4-[6-(3-Fluoro-biphenyl-4-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C236)

Compound C236 was made in a similar manner as described in Example 11.70as a white solid (51 mg, 55%). ¹H NMR (CDCl₃, 400 MHz) δ 1.28 (d, 6H),1.81-1.86 (m, 2H), 1.99-2.04 (m, 2H), 2.23 (s, 3H), 3.44-3.50 (m, 2H),3.74-3.80 (m, 2H), 4.96 (sep, 1H), 5.34-5.38 (m, 1H), 7.27 (t, 1H),7.36-7.47 (m, 5H), 7.57 (d, 2H), 8.28 (s, 1H). Exact mass calculated forC₂₆H₂₈FN₃O₄ 465.2, found 466.5.

Example 11.90 Preparation of4-[6-(2-Fluoro-4-pyridin-3-yl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C237)

Compound C237 was made in a similar manner as described in Example 11.70as a yellow solid (11 mg, 12%). ¹H NMR (CDCl₃, 400 MHz) δ 1.27 (d, 6H),1.80-1.83 (m, 2H), 1.98-2.02 (m, 2H), 2.23 (s, 3H), 3.41-3.47 (m, 2H),3.74-3.79 (m, 2H), 4.94 (sep, 1H), 5.34-5.38 (m, 1H), 7.43 (t, 1H), 7.48(d, 2H), 7.90-7.94 (m, 1H), 8.23 (s, 1H), 8.43-8.46 (m, 1H), 8.83 (d,1H), 9.12 (s, 1H). Exact mass calculated for C₂₅H₂₇FN₄O₄ 466.2, found467.6.

Example 11.91 Preparation of4-[6-(2-Fluoro-4-pyridin-4-yl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C235)

Compound C235 was made in a similar manner as described in Example 11.70as a yellow solid (13 mg, 14%). ¹H NMR (CDCl₃, 400 MHz) δ 1.27 (d, 6H),1.79-1.83 (m, 2H), 1.98-2.04 (m, 2H), 2.23 (s, 3H), 3.40-3.47 (m, 2H),3.75-3.79 (m, 2H), 4.95 (sep, 1H), 5.34-5.38 (m, 1H), 7.48 (t, 1H),7.58-7.62 (m, 2H), 8.01 (d, 2H), 8.23 (s, 1H), 8.90 (d, 2H). Exact masscalculated for C₂₅H₂₇FN₄O₄ 466.2, found 467.6.

Example 11.92 Preparation of4-[6-(2-Fluoro-4-thiophen-3-yl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C239)

Compound C239 was made in a similar manner as described in Example 11.70as a white solid (29 mg, 31%). ¹H NMR (CDCl₃, 400 MHz) δ 1.27 (d, 6H),1.78-1.83 (m, 2H), 1.97-2.01 (m, 2H), 2.21 (s, 3H), 3.40-3.47 (m, 2H),3.73-3.79 (m, 2H), 4.94 (sep, 1H), 5.34-5.36 (m, 1H), 7.22 (t, 1H), 7.34(d, 1H), 7.39-7.45 (m, 4H), 8.24 (s, 1H). Exact mass calculated forC₂₄H₂₆FN₃O₄S 471.2, found 472.4.

Example 11.93 Preparation of4-[6-(2-Fluoro-4-pyrimidin-5-yl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C238). Compound C238 was made in asimilar manner as described in Example 11.70 as a white solid (10 mg,11%). Exact mass calculated for C₂₄H₂₆FN₅O₄ 467.2, found 468.6. Example11.94 Preparation of4-{6-[2-Fluoro-4-(5-methoxy-pyridin-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester (Compound C234)

Compound C234 was made in a similar manner as described in Example 11.70as a white solid (TFA salt, 192 mg, 71%). ¹H NMR (CDCl₃, 400 MHz)1.26-1.28 (d, J=6.3 Hz, 6H), 1.77-1.83 (m, 2H), 1.98-2.06 (m, 2H), 2.23(s, 3H), 3.40-3.46 (m, 2H), 3.76-3.85 (m, 2H), 4.04 (s, 3H), 4.92-4.98(m, 1H), 5.33-5.38 (m, 1H), 7.37-7.45 (m, 3H), 7.77-7.78 (m, 1H),8.23-8.24 (d, J=4.67, 1H), 8.45-8.46 (d, J=2.3 Hz, 1H), 8.61 (s, 1H).Exact mass calculated for C₂₆H₂₉FN₄O₅ 496.21, found 497.4.

Example 11.95 Preparation of4-[6-(4-Ethynyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (Compound C240)

Pd(II)(PhCN)₂Cl₂ (15 mg, 0.039 mmol) and CuI (9 mg, 0.047 mmol) weredissolved in anhydrous dioxane (3 mL), 10 wt % P(t-Bu)₃ in hexanes(0.200 mL, 13.6 mg, 0.067 mmol), NH(i-Pr)₂, (0.085 mL, 0.60 mmol),4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (243 mg, 0.50 mmol), and TMS-acetylene (0.083 mL,0.60 mmol), were added and the reaction mixture was sealed, purged withnitrogen, and stirred at room temperature for 12 h. The reaction mixturewas diluted with EtOAc (15 mL), the mixture was filtered through asilica pad, the solvent was evaporated in vacuo at 23 C to give a darkoil which was dissolved in THF (3.5 mL) and MeOH (1.5 mL). 1.0 N NaOH(0.75 mL, 0.75 mmol) was added and after 5 min glacial AcOH (0.086 mL,1.5 mmol) was added. After addition of silica (2.4 g) the solvent wasevaporated in vacuo at 25 C to give a solid which was pulverized withmortar and pestle. This crude product was adsorbed onto silica andpurified by flash chromatography using hexanes-EtOAc, 82:18, thenhexanes-EtOAc, 75:25, v/v, to give the title Compound C240 as a resin(67 mg, 32% over 2 steps). ¹H NMR (400 HMz, CDCl₃) δ 1.25 (d, J=6 Hz,6H), 1.78 (m, 2H), 1.98 (m, 2H), 2.17 (s, 3H), 3.07 (s, 1H), 3.40 (m,2H), 3.74 (m, 2H), 4.92 (m, 1H), 5.32 (m, 1H), 7.14 (m, 1H), 7.29 (m,2H), 8.18 (s, 1H). LRMS calculated for C₂₂H₂₄FN₃O₄: 413.18. Found: 414.5(M+H).

Example 12 Syntheses of Compounds of the Present Invention Example 12.1Preparation of4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (Compound D1)

A mixture of4-{[(6-chloro-5-methyl-pyrimidin-4-yl)-cyclopropyl-amino]-methyl}-piperidine-1-carboxylicacid tent-butyl ester (200 mg, 0.5 mmole), potassium carbonate (208 mg,1.5 mmole), and 2-fluoro-4-methanesulfonyl-phenol (95 mg, 0.5 mmole) in2 mL DMF was heated under microwave irradiation at 160° C. for 4 hours.Mixture was purified by HPLC to give compound D1 as a yellow solid (93mg, 35%). ¹H NMR (CDCl₃, 400 MHz) δ 0.69-0.73 (m, 2H), 0.97-1.02 (m,2H), 1.10-1.17 (m, 2H), 1.45 (s, 9H), 1.71 (d, J=12.4 Hz, 2H), 1.98-2.07(m, 1H), 2.38 (s, 3H), 2.72 (t, J=12.4 Hz, 2H), 3.07-3.11 (m, 1H), 3.12(s, 3H), 3.52 (d, J=7.3 Hz, 2H), 4.12 (d, J=12.9 Hz, 2H), 7.45 (t, J=8.3Hz, 1H), 7.80-7.84 (m, 2H), 8.34 (s, 1H). Exact mass calculated forC₂₆H₃₅FN₄O₅S 534.2, found 535.4 (MH⁺).

Example 12.2 Preparation of4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methy)-piperidine-1-carboxylicacid isopropyl ester (Compound D2)

A mixture ofcyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-piperidin-4-ylmethyl-amine(65 mg, 0.15 mmole) and triethylamine (23 mg, 0.225 mmole) in 2 mL THFwas stirred at room temperature for 10 minutes. Into this mixture wasadded drop-wise isopropyl chloroformate (0.225 mmole). The mixture wasquenched with water, extracted with ethyl acetate, and dried in vacuumto give Compound D2 as a yellow solid (65 mg, 83%). ¹H NMR (CDCl₃, 400MHz) δ 0.69-0.64 (m, 2H), 0.83-0.88 (m, 2H), 1.12-1.15 (m, 2H), 1.23 (d,J=6.3 Hz, 6H), 1.72 (d, J=13.1 Hz, 2H), 1.94-2.02 (m, 1H), 2.04 (s, 3H),2.73 (t, J=12.4 Hz, 2H), 2.97-3.17 (m, 1H), 3.10 (s, 3H), 3.49-3.55 (m,2H), 4.09-4.23 (m, 2H), 4.90 (sept, J=6.3 Hz, 1H), 7.45 (t, J=8.3 Hz,1H), 7.76-7.80 (m, 2H), 8.12 (s, 1H). Exact mass calculated forC₂₅H₃₃FN₄O₅S 520.2, found 521.5 (MH⁺).

Example 13 Syntheses of Compounds of the Present Invention Example 13.1Preparation of4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid isopropyl ester (Compound E1) Step 1: Preparation of4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylicacid tert-butyl ester

A mixture of 4-mercapto-piperidine-1-carboxylic acid tert-butyl ester(1.5352 g, 7.06 mmol) and 4,6-dichloro-5-methyl-pyrimidine (1.1512 g,7.06 mmol) in 15 mL of THF with sodium t-butoxide (1M in THF, 8.3 mL,8.3 mmol) added dropwise. After 5 min, mixture was concentrated andresidue was extracted with CH₂Cl₂ and H₂O. Organic phase was dried overMgSO₄, filtered and concentrated to give4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylicacid tert-butyl ester as a yellowish solid (2.3469 g, 97%). Exact masscalculated for C₁₅H₂₂ClN₃O₂S 343.11, found 344.1 (MH⁺).

Step 2: Preparation of4-chloro-5-methyl-6-(piperidin-4-ylsulfanyl)-pyrimidine

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylicacid tert-butyl ester (2.3469 g, 6.82 mmol) and 40 mL of 4M HCl indioxane was stirred at room temperature over night. Mixture wasconcentrated to give4-chloro-5-methyl-6-(piperidin-4-ylsulfanyl)-pyrimidine as a yellowishsolid (1.8985 g, 99%). Exact mass calculated for C₁₀H₁₄ClN₃S 243.06,found 244.1 (MH⁺).

Step 3: Preparation of4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylicacid isopropyl ester

A mixture of 4-chloro-5-methyl-6-(piperidin-4-ylsulfanyl)-pyrimidine(HCl salt, 1.8985 g, 6.77 mmol) and triethylamine (2.825 mL, 0.02 mol)in 50 mL of CH₃CN was stirred under room temperature. After 15 min,isopropyl chloroformate (1M in toluene, 8.13 mL, 8.13 mmol) were addedslowly under 0° C. Mixture was stirred under room temperature. After 3h, mixture was concentrated and residue was extracted with EtOAc andsaturated NaHCO₃. Organic phase was dried over MgSO₄, filtered andconcentrated to give4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylicacid isopropyl ester as yellowish oil (1.9143 g, 85%). Exact masscalculated for C₁₄H₂₀ClN₃O₂S 329.1, found 330.3 (MH⁺).

Step 4: Preparation of4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid isopropyl ester (Compound E1)

A mixture of4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylicacid isopropyl ester (1.2234 g, 3.7 mmol),2-fluoro-4-methanesulfonyl-phenylamine (702 mg, 3.7 mmol), palladiumacetate (84.3 mg, 0.37 mmol), 2-(di-t-butylphosphino)biphenyl (11 mg,0.037 mmol), and sodium tert-butoxide (891.8 mg, 9.28 mmol) in 15 mL1,4-dioxane was heated in microwave for 2 hours at 120° C. The mixturewas purified by HPLC to give Compound E1 as a tanned solid (TFA salt,601.1 mg, 27%). ¹H NMR (MeOH-d₄, 400 MHz) δ 1.16-1.17 (d, J=6.32 Hz,6H), 1.49-1.58 (m, 2H), 2.00-2.04 (m, 2H), 2.14 (s, 3H), 3.07 (s, 3H),3.21-3.23 (m, 2H), 3.90-3.94 (m, 2H), 4.01-4.08 (m, 1H), 4.75-4.81 (m,1H), 7.66-7.68 (d, J=8.08 Hz, 2H), 8.01-8.05 (m, 1H), 8.27 (s, 1H).Exact mass calculated for C₂₁H₂₇FN₄O₄S₂ 482.15, found 483.4 (MH⁺).

Example 14 Protocol for RUP3 Dose Responses in Melanophores

Melanophores are maintained in culture as reported by Potenza, M. N. andLerner, M. R., in Pigment Cell Research, Vol. 5, 372-378, 1992 andtransfected with the RUP3 expression vector (pCMV) usingelectroporation. Following electroporation, the transfected cells areplated into 96 well plates for the assay. The cells are then allowed togrow for 48 hours in order to both recover from the electroporationprocedure and attain maximal receptor expression levels.

On the assay day, the growth medium on the cells is replaced withserum-free buffer containing 10 nM melatonin. The melatonin acts via anendogenous Gi-coupled GPCR in the melanophores to lower intracellularcAMP levels. In response to lowered cAMP levels, the melanophorestranslocate their pigment to the center of the cell. The net effect ofthis is a significant decrease in the absorbance reading of the cellmonolayer in the well, measured at 600-650 nM.

After a 1-hour incubation in melatonin, the cells become completelypigment-aggregated. At this point a baseline absorbance reading iscollected. Serial dilutions of test compounds are then added to theplate and compounds that stimulate RUP3 produce increases inintracellular cAMP levels. In response to these increased cAMP levels,the melanophores translocate their pigment back into the cell periphery.After one hour, stimulated cells are fully pigment-dispersed. The cellmonolayer in the dispersed state absorbs much more light in the 600-650nm range. The measured increase in absorbance compared to the baselinereading allows one to quantitate the degree of receptor stimulation andplot a dose-response curve.

The compounds in the above examples were screened using the melanophoreassay. Representative compounds and their corresponding EC₅₀ values areshown in the Table 8 below:

TABLE 8 RUP3 (EC₅₀) Compound (nM) A11 86 A14 242 A24 185 A27 76.5 A3243.5 A39 16.9 A90 52 B4 300 C168 28.3

Other compounds in the Examples showed EC₅₀ activities in the membranecyclase assay less than about 10 μM.

Example 15 Food Intake Study

Male ZDF (Zucker diabetic fatty) rats weighing 350 g-400 g were dosedindependently with two structurally divergent chemotypes exhibitingagonism to the RUP3 receptor. Rats were dosed daily via oral gavage witheither vehicle (100% PEG 400), First Compound (30 mg/kg, 100 mg/kg), orSecond Compound (10 mg/kg, 30 mg/kg) at a volume of 3 ml/kg. Body weightand food intake were monitored and recorded daily. The table shown belowillustrates the body weight (g) and cumulative food intake (g) takenafter both seven days and 14 days of dosing.

Cumulative Food Dose Intake (g) Body Weight (g) Substance (mg/Kg) Week 1Week 2 Week 1 Week 2 First Vehicle 321 672 390 395 Compound 30 mg/Kg 271557 383 383 100 mg/Kg  211 457 361 376 Second Vehicle 261 563 393 393Compound 10 mg/Kg 217 459 388 390 30 mg/Kg 159 307 377 373

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications, and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate or solvate, or N-oxidethereof; wherein: A and B are each independently C₁₋₃ alkyleneoptionally substituted with 1 to 4 substituents selected from the groupconsisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyland halogen; D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂; E is N, C or CR₄;

is a single bond when E is N or CR₄, or a double bond when E is C; V₁ isselected from the group consisting of C₁₋₃ alkylene, ethynylene and C₁₋₂heteroalkylene optionally substituted with 1 to 4 substituents selectedfrom the group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano,C₁₋₃ haloalkyl and halogen; or V₁ is a bond; V₂ is C₃₋₆ cycloalkylene orC₁₋₃ alkylene wherein each are optionally substituted with 1 to 4substituents selected from the group consisting of C₁₋₃ alkyl, C₁₋₄alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen; or V2 is a bond; Wis NR_(S), O, S, S(O) or S(O)₂; or W is absent; Q is NR₆, O, S, S(O) orS(O)₂; X is N or CR₇; Y is N or CR₈; Z is selected from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylthiocarboxamide,C₁₋₄ alkylsulfonamide, C₁₋₄ allylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₁₋₄ dialkylamino, carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₄₋₈ diacylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ diallylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₂₋₆ dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl, heterocyclic,heteroaryl, hydroxyl, hydroxycarbamimidoyl, hydroxylamino, nitro andtetrazolyl, wherein C₁₋₈ alkyl, C₃₋₇ cycloalkyl, and heterocyclic areeach optionally substituted with 1, 2, 3 or 4 groups selected from thegroup consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₇ alkyl,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro, andwherein said C₁₋₇ alkyl is optionally substituted with amino; or Z is agroup of Formula (A):

wherein: R₉ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl; and R₁₀ is H, nitro ornitrile; Ar₁ is aryl or heteroaryl each optionally substituted with R₁₁,R₁₂, R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the groupconsisting of C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino,C₂₋₆-dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, guanidinyl,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, and thiol, and wherein C₁₋₅ acyl,C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,heteroaryl, phenoxy and phenyl are optionally substituted with 1 to 5substituents selected independently from the group consisting of C₁₋₅acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyloxy, dialkylamino, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heteroaryl, heterocyclic,hydroxyl, nitro, phenyl, and phosphonooxy, wherein said C₁₋₇ alkyl andC₁₋₄ alkylcarboxamide are each optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₄ alkoxy andhydroxy; or R₁₁ is a group of Formula (B):

wherein: “p” and “r” are each independently 0, 1, 2 or 3; and R₁₆ is H,C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,cyano, C₃₋₇ cycloalkyl, C₁₋₆ dialkylcarboxamide, halogen, heteroaryl orphenyl, and wherein the heteroaryl or phenyl optionally substituted with1 to 5 substituents selected independently from the group consisting ofC₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₁₋₆ alkynyl, C₂₋₈ dialkylamino,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl; and R₁₂, R₁₃,R₁₄, and R₁₅ are each independently selected form the group consistingof C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyland nitro; or two adjacent groups selected from the group consisting ofR₁₂, R₁₃, R₁₄ and R₁₅ together with the atoms to which they are attachedform a 5-, 6- or 7-membered cycloalkyl, cycloalkenyl or heterocyclicgroup fused with Ar₁, wherein the 5-, 6- or 7-membered group isoptionally substituted with halogen; R₁, R₇ and R₈ are eachindependently selected from the group consisting of H, C₁₋₅ acyloxy,C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈dialkylamino, carboxamide, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkylthio and hydroxyl; R₂ is selected from the group consisting ofC₁₋₈ alkyl, amino, aryl, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl and hydroxyl; andwherein C₁₋₈ alkyl, aryl or heteroaryl optionally substituted with 1 to5 substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, dialkylsulfonamide,C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino and nitro;or R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are each independently aryl orheteroaryl optionally substituted with 1 to 5 substituents selected fromthe group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino, C₁₋₄alkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆-cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or R₂ is agroup of Formula (C):

wherein: R₁₇ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl orOR₁₉; and R₁₈ is F, Cl, Br, CN or NR₂₀R₂₁; where R₁₉ is H, C₁₋₈ alkyl orC₃₋₇ cycloalkyl, and R₂₀ and R₂₁ are each independently H, C₁₋₈ alkyl,C₃₋₇ cycloalkyl, aryl or heteroaryl; or R₂ is a group of Formula (D):

wherein: G is: i) —C(O)—, —C(O)NR₂₃—, —C(O)O—, —OC(O)NR₂₃—, —NR₂₃C(O)O—,—OC(O)—C(S)—, —C(S)NR₂₃—, —C(S)O—, —OC(S)—, —CR₂₃R₂₄—, —O—, —S—, —S(O)—or —S(O)₂— when D is CR₂R₃, or ii) —CR₂₃R₂₄C(O)—, —C(O)—,—CR₂₃R₂₄C(O)NR₂₅—, —C(O)NR₂₃—, —C(O)O—, —C(S)—, —C(S)NR₂₃—, —C(S)O—,—CR₂₃R₂₄—, —S(O)₂—, or a bond when D is NR₂, wherein R₂₃, R₂₄ and R₂₅are each independently H or C₁₋₈ alkyl; and R₂₂ is H, C₁₋₈ alkyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, or heterocyclic eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇alkyl, C₁₋₄ alkylamino, C₁₋₄ alIcylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ allylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heteroaryl, heterocyclic,hydroxyl, hydroxylamino, nitro, phenyl, phenoxy, and sulfonic acid,wherein said C₁₋₇ alkyl, heteroaryl, phenyl and phenoxy are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₅-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, and nitro; R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy or hydroxyl;and R₄, R₅ and R₆ are each independently H, C₁₋₈ alkyl or C₃₋₇cycloalkyl, wherein said C₁₋₈ alkyl is optionally substituted with C₁₋₄alkoxy, C₃₋₇ cycloalkyl, or heteroaryl.
 2. The compound according toclaim 1 wherein X is N.
 3. The compound according to claim 1 wherein Yis N.
 4. The compound according to claim 1 wherein X and Y or both N. 5.The compound according to claim 1 wherein

is a single bond.
 6. The compound according to claim 1 wherein W is NH.7. The compound according to claim 1 wherein W is O.
 8. The compoundaccording to claim 1 wherein Q is NR₆.
 9. The compound according toclaim 5 wherein R₆ is C₁₋₈ alkyl.
 10. The compound according to claim 5wherein, R₆ is C₃₋₇ cycloalkyl.
 11. The compound according to claim 5wherein R₆ is H.
 12. The compound according to claim 1 wherein Q is O.13. The compound according to claim 1 wherein Q is S.
 14. The compoundaccording to claim 1 wherein both A and B are —CH₂—.
 15. The compoundaccording to claim 1 wherein A is —CH₂CH₂— and B is —CH₂—.
 16. Thecompound according to claim 1 wherein both A and B are —CH₂CH₂—.
 17. Thecompound according to claim 1 wherein V, is a bond.
 18. The compoundaccording to claim 1 wherein V₂ is a —CH₂— or —CH₂CH₂— group.
 19. Thecompound according to claim 1 wherein V₁ is a bond.
 20. The compoundaccording to claim 1 wherein D is N—R₂.
 21. The compound according toclaim 1 wherein R₂ is a group of Formula (D):

wherein: G is —CR₁₃R₂₄C(O)—, —C(O)—, —CR₂₃R₂₄C(O)NR₂₃—, —C(O)NR₂₃—,—C(O)O—, —C(S)—, —C(S)NR₂₃—, —C(S)O—, —CR₂₃R₂₄—, —S(O)₂—, or a bond;wherein R₂₃ and R₂₄ are each independently H or C₁₋₈ alkyl; and R₂₂ isH, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, or heterocyclic eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heteroaryl, heterocyclic,hydroxyl, hydroxylamino, nitro, phenyl, phenoxy, and sulfonic acid,wherein said C₁₋₇ alkyl, phenyl and phenoxy are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, diallylcarboxamide,C₂₋₆ dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl,C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heterocyclic, hydroxyl, hydroxylamino, and nitro.
 22. The compoundaccording to claim 1 wherein R₂ is —C(O)OR₂₂ and R₂₂ is C₁₋₈ alkyl, C₃₋₇cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino,carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic,hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl,phenyl and phenoxy are each optionally substituted with 1 to 5substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.
 23. The compound according to claim 1wherein R₂ is —C(O)OR₂₂ and R₂₂ is C₁₋₈ alkyl, or C₃₋₇ cycloalkyl eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, carboxy,cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy,and sulfonic acid.
 24. The compound according to claim 1 wherein R₂ is—C(O)OR₂₂ and R₂₂ is C₁₋₈ alkyl, or C₃₋₇ cycloalkyl wherein said C₃₋₇cycloalkyl is optionally substituted with 1 to 5 substituents selectedfrom the group consisting of C₁₋₄ alkoxy, C₁₋₇ alkyl, carboxy, C₂₋₈dialkylamino, and halogen.
 25. The compound according to claim 1 whereinR₂ is —C(O)OR₂₂ and R₁₂ is C₁₋₈ alkyl, or C₃₋₇ cycloalkyl.
 26. Thecompound according to claim 1 wherein R₂ is —C(O)R₂₂ and R₂₂ is C₁₋₈alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, or heterocyclic eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇, alkyl, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen,heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy, and sulfonic acid,wherein said C₁₋₇ alkyl, phenyl and phenoxy are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof amino, C₁₋₄ haloalkoxy, and heterocyclic.
 27. The compound accordingto claim 1 wherein R₂ is —C(O)R₂₂ and R₂₂ is C₁₋₈ alkyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of H, C₁₋₄ alkoxy, C₁₋₇ alkyl, amino,carboxy, halogen, heteroaryl, hydroxyl, phenoxy, and sulfonic acid,wherein said C₁₋₇ alkyl and phenoxy are optionally substituted with 1 to5 substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.
 28. The compound according to claim 1wherein R₂ is —CH₂R₂₂, or —R₂₂ and R₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl,phenyl, heteroaryl, or heterocyclic each optionally substituted with 1to 5 substituents selected from the group consisting of C₁₋₅ acyl, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino,carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic,hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl,phenyl and phenoxy are each optionally substituted with 1 to 5substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.
 29. The compound according to claim 1wherein R₂ is —CH₂R₂₂, or —R₂₂, and R₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl,or heteroaryl each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₄alkoxy, carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, andhydroxyl.
 30. The compound according to claim 1 wherein R₂ is —S(O)₂R₂₂and R₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇,alkyl, C₁₋₄ alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy, andsulfonic acid, wherein said C₁₋₇ alkyl, phenyl and phenoxy are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of amino, C₁₋₄ haloalkoxy, and heterocyclic.
 31. The compoundaccording to claim 1 wherein R₂ is —S(O)₂R₂₂ and R₂₂ is C₁₋₈ alkyl, orheteroaryl and said heteroaryl is optionally substituted with 1 to 5C₁₋₇ alkyl.
 32. The compound according to claim 1 wherein R₂ is—CR₂₃R₂₄C(O)R₂₂ and wherein R₂₃ and R₂₄ are each independently H or C₁₋₈alkyl; and R₂₂ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇alkyl, C₁₋₄ alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,halogen, heteroaryl, heterocyclic, hydroxyl, phenyl, phenoxy, andsulfonic acid, wherein said C₁₋₇ alkyl, phenyl and phenoxy are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of amino, C₁₋₄ haloalkoxy, and heterocyclic.
 33. The compoundaccording to claim 1 wherein R₂ is —CR₂₃R₂₄C(O)R₂₂ and wherein R₂₃ andR₂₄ are each independently H or C₁₋₈ alkyl; and R₂₂ is phenyl,heteroaryl, or heterocyclic each optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₄ alkoxy, C₁₋₇alkyl, C₁₋₄ alkylsulfonyl, cyano, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, halogen, heteroaryl, and phenyl.
 34. The compoundaccording to claim 1 wherein R₂ is —CR₂₃R₂₄C(O)NR₂₅R₂₂ and wherein R₂₃,R₂₄ and R₂₅ are each independently H or C₁₋₈ alkyl; and R₂₂ is C₁₋₈alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, or heterocyclic eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl,amino, carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl,heterocyclic, hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein saidC₁₋₇ alkyl, phenyl and phenoxy are each optionally substituted with 1 to5 substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic.
 35. The compound according to claim 1wherein R₂ is —CH₂C(O)NHR₂₂ and wherein R₂₂ is phenyl optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ haloalkyl, and halogen.
 36. Thecompound according to claim 1 wherein Ar₁ is aryl or heteroaryl eachoptionally substituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅; wherein R₁₁ isselected from the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino,carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆ dialkylamino, halogen,heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,heteroaiylcarbonyl, and sulfonamide, and wherein C₁₋₆ acylsulfonamide,C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylsulfonamide,alkylsulfonyl, C₁₋₄ alkylthio, carbamimidoyl, C₂₋₆ dialkylamino,heterocyclic, heterocyclic-carbonyl, and heteroaryl are each optionallysubstituted with 1 to 5 substituents selected independently from thegroup consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₃₋₇ cycloalkyloxy, C₂₋₆dialkylamino, C₂₋₆ dialkylcarboxamide, heteroaryl, heterocyclic,hydroxyl, phenyl, and phosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄alkylcarboxamide are each optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₄ alkoxy andhydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected formthe group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, carbamimidoyl, carboxamide, cyano,C₂₋₆ dialkylamino, and halogen.
 37. The compound according to claim 36wherein Ar₁ is aryl.
 38. The compound according to claim 36 wherein Ar₁is heteroaryl.
 39. The compound according to claim 1 wherein Ar₁ isphenyl optionally substituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅; whereinR₁₁ is selected from the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino,carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆ dialkylamino, halogen,heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, and sulfonamide, and wherein C₁₋₆ acylsulfonamide,C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carbamimidoyl, C₂₋₆ dialkylamino,heterocyclic, heterocyclic-carbonyl, and heteroaryl are each optionallysubstituted with 1 to 5 substituents selected independently from thegroup consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₃₋₇ cycloalkyloxy, C₂₋₆dialkylamino, C₂₋₆ dialkylcarboxamide, heteroaryl, heterocyclic,hydroxyl, phenyl, and phosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄alkylcarboxamide are each optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₄ alkoxy andhydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected formthe group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, carbamimidoyl, carboxamide, cyano,C₂₋₆ dialkylamino, and halogen.
 40. The compound according to claim 1wherein Ar₁ is phenyl optionally substituted with R₁₁, R₁₂, R₁₃, R₁₄,and R₁₅; wherein R₁₁ is selected from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₅ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆dialkylamino, halogen, heterocyclic, heterocyclic-oxy,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and sulfonamide,and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ areeach independently selected form the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide, cyano, dialkylamino, andhalogen.
 41. The compound according to claim 1 wherein Ar₁ is phenyloptionally substituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅; wherein R₁₁ isselected from the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carbamimidoyl,carboxamide, carboxy, cyano, C₂₋₆ dialkylamino, halogen, heterocyclic,heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl,and sulfonamide, and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ areeach independently selected form the group consisting of C₁₋₈ alkyl, andhalogen.
 42. The compound according to claim 1 wherein Ar₁ is pyridyloptionally substituted with R₁₁, R₁₂, R₁₃, and R₁₄; wherein R₁₁ isselected from the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, amino,carbamimidoyl, carboxamide, carboxy, cyano, C₂₋₆ dialkylamino, halogen,heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl, andsulfonamide, and wherein C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylamino, C₁₋₄ alkylsulfonamide, alkylsulfonyl, C₁₋₄ alkylthio,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,and heteroaryl are each optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, carboxy, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆diallylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, and R₁₄ are eachindependently selected form the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide, cyano, C₂₋₆ dialkylamino,and halogen.
 43. The compound according to claim 1 wherein Ar₁ ispyridyl optionally substituted with R₁₁, R₁₂, R₁₃, and R₁₄; wherein R₁₁is selected from the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio,amino, C₂₋₆ dialkylamino, halogen, heterocyclic, and sulfonamide, andwherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, alkylsulfonyl, C₁₋₄alkylthio, C₂₋₆ dialkylamino, and heterocyclic are each optionallysubstituted with 1 to 5 substituents selected independently from thegroup consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₄alkylsulfonyl, C₃₋₇ cycloalkyloxy, heteroaryl, hydroxyl, phenyl, andphosphonooxy; and R₁₂, R₁₃, and R₁₄ are each independently selected formthe group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, carbamimidoyl, carboxamide, cyano,C₂₋₆ dialkylamino, and halogen.
 44. The compound according to claim 1wherein Ar₁ is pyridyl optionally substituted with R₁₁, R₁₂, R₁₃, andR₁₄; wherein R₁₁ is selected from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, C₂₋₆ dialkylamino, halogen,heterocyclic, and sulfonamide, and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, alkylsulfonyl, C₁₋₄ alkylthio, C₂₋₆ dialkylamino, andheterocyclic are each optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₄ alkylsulfonyl, C₃₋₇ cycloalkyloxy,heteroaryl, hydroxyl, phenyl, and phosphonooxy; and R₁₂, R₁₃, and R₁₄are each independently selected form the group consisting of C₁₋₈ alkyl,and halogen.
 45. The compound according to claim 1 wherein Z is selectedfrom the group consisting of C₁₋₅ acyl, C₁₋₈ alkyl, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, amino, carbamimidoyl, cyano, C₃₋₇ cycloalkyl,heterocyclic, and hydroxycarbamimidoyl, wherein C₁₋₈ alkyl, C₃₋₇cycloalkyl, and heterocyclic are each optionally substituted with 1, 2,3 or 4 groups selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,halogen, hydroxyl, hydroxylamino and nitro, and wherein said C₁₋₇ alkylis optionally substituted with amino.
 46. The compound according toclaim 1 wherein Z is selected from the group consisting of C₁₋₅ acyl,C₁₋₈ alkyl, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, amino, carbamimidoyl,cyano, C₃₋₇ cycloalkyl, heterocyclic, and hydroxycarbamimidoyl, whereinsaid heterocyclic is optionally substituted with a —CH₂NH₂ group. 47.The compound according to claim 1 wherein Z is selected from the groupconsisting of C(O)CH₃, C(O)CH₂CH₃, CH₃, CH₂CH₃, C≡CH, NHS(O)₂CH₃, amino,carbamimidoyl, cyano, cyclopropyl, 4,5-dihydro-1H-imidazol-2-yl,5-aminomethyl-4,5-dihydro-oxazol-2-yl, and hydroxycarbamimidoyl.
 48. Thecompound according to claim 1 wherein: A and B are each independently—CH₂CH₂— or —CH₂—; D is N—R₂; V₁ is a bond; V₂ is —CH₂—, —CH₂CH₂—, or abond; W and Q are each independently NH or O; X and Y are eachindependently N or CH, provided that if either X or Y is CH then theother is N; Z is selected from the group consisting of nitro, C₁₋₅ acyl,C₁₋₈ alkyl, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, amino, carbamimidoyl,cyano, C₃₋₇ cycloalkyl, heterocyclic, and hydroxycarbamimidoyl, whereinsaid heterocyclic is optionally substituted with a —CH₂NH₂ group; R₂ is—C(O)OR₂₂, —C(O)R₂₂, —CH₂R₂₂, —R₂₂, —S(O)₂R₂₂, —CR₂₃R₂₄C(O)R₂₂, or—CR₂₃R₂₄C(O)NR₂₅R₂₂, wherein R₂₂ is C₁₋₈ alkyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl, amino,carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, heterocyclic,hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl,phenyl and phenoxy are each optionally substituted with 1 to 5substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic; and R₂₃ and R₂₄ are each independently Hor C₁₋₈ alkyl; Ar₁ is aryl or heteroaryl each optionally substitutedwith R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, amino, carbamimidoyl, carboxamide,carboxy, cyano, C₂₋₆ dialkylamino, halogen, heterocyclic,heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl, and sulfonamide,and wherein C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₄ alkylsulfonamide, alkylsulfonyl, C₁₋₄ alkylthio,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,and heteroaryl are each optionally substituted with 1 to 5 substituentsselected independently from the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, carboxy, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ areeach independently selected form the group consisting of C₁₋₆acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxamide, cyano, dialkylamino, andhalogen.
 49. The compound according to claim 1 wherein: A and B are both—CH₂CH₂—; D is N—R₂; V₁ and V₂ are both a bond; W and Q are eachindependently NH or O; X and Y are both N; Z is selected from the groupconsisting of nitro, C(O)CH₃, C(O)CH₂CH₃, CH₃, CH₂CH₃, C≡CH, NHS(O)₂CH₃,amino, carbamimidoyl, cyano, cyclopropyl, 4,5-dihydro-1H-imidazol-2-yl,5-aminomethyl-4,5-dihydro-oxazol-2-yl, and hydroxycarbamimidoyl; R₂ is—C(O)OR₂₂, wherein R₂₂ is C₁₋₈ alkyl, or C₃₋₇ cycloalkyl each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfonyl, amino, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,halogen, and hydroxyl; Ar₁ is phenyl optionally substituted with R₁₁,R₁₂, R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, carbamimidoyl, carboxamide, carboxy,cyano, C₂₋₆ dialkylamino, halogen, heterocyclic, heterocyclic-oxy,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, and sulfonamide,and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ areeach independently selected form the group consisting of C₁₋₈ alkyl, andhalogen.
 50. The compound according to claim 1 wherein: A and B are both—CH₂CH₂—; D is N—R₂; V₁ and V, are both a bond; W is NH; Q is O; X and Yare both N; Z is nitro, cyano, C(O)CH₃, amino, CH₃, CH₂CH₃, or C≡CH; R₂is —C(O)OR₂₂, —C(O)R₂₂, or —S(O)₂R₂₂ wherein is C₁₋₈ alkyl, C₃₋₇cycloalkyl, phenyl, heteroaryl, or heterocyclic each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylsulfonyl,amino, carbo-C₁₋₆-alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylamino, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl,heterocyclic, hydroxyl, phenyl, phenoxy, and sulfonic acid, wherein saidC₁₋₇ alkyl, phenyl and phenoxy are each optionally substituted with 1 to5 substituents selected from the group consisting of amino, C₁₋₄haloalkoxy, and heterocyclic; Ar₁ is phenyl, 3-pyridyl, or 2-pyridyleach optionally substituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅, whereinR₁₁ is selected from the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, carbamimidoyl,carboxamide, carboxy, cyano, C₂₋₆ dialkylamino, halogen, heterocyclic,heterocyclic-oxy, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl,and sulfonamide, and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic,heterocyclic-carbonyl, and heteroaryl are each optionally substitutedwith 1 to 5 substituents selected independently from the groupconsisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylcarboxamide, C₁₋₄ alkylsulfonyl, carboxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, heteroaryl, heterocyclic, hydroxyl, phenyl, andphosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are eachoptionally substituted with 1 to 5 substituents selected from the groupconsisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅ areeach independently CH₃, or F.
 51. The compound according to claim 1wherein: A and B are both —CH₂CH₂—; D is N—R.,; V₁ and V, are both abond; W and Q are both O; X and Y are both N; Z is selected from thegroup consisting of CH₃, CH₂CH₃, cyclopropyl, or C≡CH; R₂ is —C(O)OR₂₂,—C(O)R₂₂, —R₂₂, —CH₂C(O)R₂₂, or —CH₂C(O)NHR₂₂, wherein R₂₂ is C₁₋₈alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylsulfonyl, amino, carboxy, cyano, C₂₋₈ dialkylamino, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, hydroxyl, phenyl, andphenoxy, wherein said C₁₋₇ alkyl, is optionally substituted with 1 or 2substituents selected from the group consisting of C₁₋₄ haloalkoxy, andheterocyclic; Ar₁ is phenyl, 2-pyridyl, or 3-pyridyl each optionallysubstituted with R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅, wherein R₁₁ is selectedfrom the group consisting of C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, amino, carbamimidoyl, carboxy, cyano, C₂₋₆ dialkylamino,halogen, heterocyclic, heterocyclic-oxy, heterocyclic-carbonyl,heteroatyl, and sulfonamide, and wherein C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio,C₂₋₆ dialkylamino, and heteroaryl are each optionally substituted with 1to 5 substituents selected independently from the group consisting ofC₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, heteroaryl, hydroxyl,and phosphonooxy wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide areeach optionally substituted with 1 to 5 substituents selected from thegroup consisting of C₁₋₄ alkoxy and hydroxy; and R₁₂, R₁₃, R₁₄, and R₁₅are each independently selected form the group consisting of C₁₋₈ alkyl,and halogen.
 52. The compound according to claim 48 wherein R₂ isselected from the group consisting of methoxycarbonyl, ethoxycarbonyl,iso-propoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl,tent-butoxycarbonyl, iso-butoxycarbonyl, and n-pentyloxycarbonyl. 53.The compound according to claim 48 wherein R₁₁ is selected from thegroup consisting of sulfamoyl, acetylsulfamoyl, propionylsulfarnoyl,butyrylsulfamoyl, pentanoylsulfamoyl, methanesulfonyl, ethanesulfonyl,propane-1-sulfonyl, hydroxymethyl; 2-hydroxyethyl; 3-hydroxypropyl;4-hydroxy-butyl; phosphonooxymethyl; 2-phosphonooxy-ethyl;3-phosphonooxy-propyl; and 4-phosphonooxy-butyl.
 54. The compoundaccording to claim 1 wherein said compound is selected from the groupconsisting of:3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;[6-(1-Hexyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;[6-(1-Cyclopropylmethyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-isopropyl-5-methyl-cyclohexyl ester;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-3-yl-methanone;(2-Chloro-pyridin-3-yl)-{4-[6-(4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-2-yl-methanone;(4-Methanesulfonyl-phenyl)-[6-(1-methanesulfonyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-5-nitro-6-[1-(propane-1-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl-amine;{6-[1-(Butane-1-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[1-(thiophene-2-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yloxy}-5-nitro-pyrimidin-4-yl-amine;{6-[1-(2,4-Dimethyl-thiazole-5-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;4-[5-Cyano-6-(3-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methanesulfonyl-pyridin-3-ylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Amino-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester;4-(4-Methanesulfonyl-phenylamino)-6-[1-(tetrahydro-furan-2-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile;4-[1-(3,3-Dimethyl-2-oxo-butyl)-piperidin-4-yloxy]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile;4-(4-Methanesulfonyl-phenylamino)-6-[1-(pyridine-3-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile;4-(1-Formyl-piperidin-4-yloxy)-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrileand4-(4-Methanesulfonyl-phenylamino)-6-[1-(pyridine-2-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile;or a pharmaceutically acceptable salt, hydrate or solvate thereof. 55.The compound according to claim 1 wherein said compound is selected fromthe group consisting of:4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine;1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-1-one;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-pyridin-2-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]-amine;{6-[1-(3,3-Dimethyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{6-[1-(3-methyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy)-pyrimidin-4-yl]-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester;1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one;{6-[1-(2-Ethoxy-ethyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester;4-{2-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester;3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester and3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester; or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 56. The compound according to claim 1 wherein saidcompound is selected from the group consisting of:4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tent-butyl ester;N-(4-Methanesulfonyl-phenyl)-5-nitro-N′-piperidin-4-yl-pyrimidine-4,6-diamine;1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-ethanoneand1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-2,2-dimethyl-propan-1-one;or a pharmaceutically acceptable salt, hydrate or solvate thereof. 57.The compound according to claim 1 wherein said compound is selected fromthe group consisting of:4-[6-(4-Cyano-2-fluoro-phenylamino)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-ylamino}-3-fluoro-benzonitrile;{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;4-{6-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-sulfamoyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Fluoro-ethyl)-2-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[4-Fluoro-6-(2-isopropoxy-ethyl)-pyridin-3-ylamino]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-[1,2,4]triazol-1-yl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[2-fluoro-4-(4-methoxy-pyridin-2-yl)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-propionylsulfamoyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-{6-[2,3-Difluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 58. The compound according to claim 1 wherein saidcompound is selected from the group consisting of:4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester;1-[4-(1-Benzyl-azetidin-3-yloxy)-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone;4-[5-Cyano-6-(6-propylamino-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-isopropylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(6-propyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylis acid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethylsulfanyl)-2-fluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethanesulfonyl)-2-fluoro-phenylamino]-3-oxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(3-methyl-butylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-morpholin-4-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethylamino)-2-fluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(4-dimethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(2-pyrrolidin-1-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-morpholin-4-yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-propylamino-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methoxy-ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(2-methanesulfonyl-ethyl)-methyl-amino]-phenylamino}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-fluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-morpholin-4-yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(2-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-(4,5-Dihydro-1H-imidazol-2-yl)-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidin-4-yl}-amine;4-[6-(2-Fluoro-4-propoxy-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-4-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-(N-hydroxycarbamimidoyl)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Carbamimidoyl-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(4-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethoxy)-4-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-methoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylsulfamoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(N-hydroxycarbamimidoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoyl-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[(2-Fluoro-4-methanesulfonyl-phenyl)-(2-methoxy-ethyl)-amino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamimidoyl-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Ethoxy-ethoxy)-2-fluoro-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-pyran-4-yloxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-hydroxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;4-{6-[2-Fluoro-4-(pyridin-2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-3-methyl-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-4-fluoro-pyridin-3-ylamino)-5-cyano-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; and4-[5-Amino-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 59. The compound according to claim 1, of the formula:4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester; or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 60. The compound according to claim 1 wherein saidcompound is selected from the group consisting of:4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-methoxy-propyl)-piperidin-4-yloxy]-5-methyl-pyrimidine;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-2-ol;4-{6-[2-Fluoro-4-(5-isopropoxymethyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(5-methoxy-pyridin-2-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Cyclopropoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(pyridine-2-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methanesulfonylamino-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methoxy-6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-(4-trifluoromethoxy-phenoxy)-propan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-(4-trifluoromethoxy-phenoxy)-ethanone;N-(4-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;N-(3-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;N-(3,5-Dichloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(4-trifluoromethyl-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-phenyl-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy}-piperidin-1-yl]-N-(4-isopropyl-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(4-methoxy-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(3-trifluoromethyl-phenyl)-acetamide;4-{6-[2-Fluoro-4-(3-methoxy-propane-1-sulfonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methyl-6-[2-methyl-6-(2-pyridin-2-yl-ethoxy)-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(thiophene-2-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{6-[(2-Isopropoxy-ethyl)-methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Amino-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(3-methyl-butyl)-piperidin-4-yloxy]-pyrimidine;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-morpholin-4-yl-ethanone;1-(3,4-Dichloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(3-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-3-yl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-phenyl-ethanone;1-(2,4-Dimethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(4-methyl-pentyl)-piperidin-4-yloxy]-pyrimidine;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-isopropoxy-propan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-isopropoxy-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-hydroxy-propan-1-one;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(5-pyridin-2-yl-thiophen-2-yl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(5-methyl-hexyl)-piperidin-4-yloxy]-pyrimidine;3-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-oxo-propane-1-sulfonic acid2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-2-yl-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(1-pentyl-piperidin-4-yloxy)-pyrimidine;4-(1-Butyl-piperidin-4-yloxy)-6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidine;4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-cyclohexanecarboxylicacid;1-(4-Diethylamino-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(2-methyl-4-phenyl-furan-3-yl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-(1-hexyl-piperidin-4-yloxy)-5-methyl-pyrimidine;4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butyricacid;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-6-methyl-heptan-2-one;5-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-pentanoicacid;5-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-pentanenitrile;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-pyridin-2-yl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-4-yl-ethanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-ylmethyl}-acrylicacid;1-[1,4]Dioxan-2-yl-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(2,3-Dihydro-[1,4]dioxin-2-yl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-yl-tolyl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-methoxy-phenyl)-ethanone;1-(2-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;3-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetyl)-benzonitrile;1-(2,4-Dimethyl-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Chloro-3-methyl-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Difluoromethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(5-phenyl-thiophen-2-yl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-2-yl-ethanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-aceticacid ethyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy}-piperidin-1-yl]-3-methoxy-propan-2-ol;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(4-methoxy-cyclohexyl)-piperidin-4-yloxy]-5-methyl-pyrimidine;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-1-one;4-{6-[2-Fluoro-4-(2-isobutoxy-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Cyclopropoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Ethoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(3-methoxy-propoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-pyridin-2-yl-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-pyran-4-yloxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-tert-Butoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-sulfo-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-trifluoromethoxy-phenoxy)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-trifluoromethoxy-phenoxy)-5-prop-1-ynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-methoxy-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(6-methoxy-4-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[6-(2-isopropoxy-ethyl)-2-methyl-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-fluoro-phenoxy)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6(2-fluoro-4-[1,2,4]triazol-4-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yloxy]-piperidin-1-yl}-3-pyridin-2-yl-propan-1-one;4-{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yloxy}-3-fluoro-benzonitrile;5-Ethynyl-4-(2-fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidine;4-[1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-ethynyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidine;4-[1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidine;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidine;4-[6-(2-Fluoro-4-methanesulfonylamino-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;cis-{-4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-carbamicacid isopropyl ester;trans-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-carbamicacid isopropyl ester;N-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-3-methyl-butyramide;N-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-isobutyramide;4-{6-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-Fluoro-6-(2-methanesulfonyl-ethyl)-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyclopropyl-6-[2,5-difluoro-4-(2-hydroxy-ethyl)-phenoxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(5-Cyclopropyl-6-{2,5-difluoro-4-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-morpholin-4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Fluoro-ethyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(1-hydroxy-cyclopropylmethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;(R)-4-(6-{2-Fluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(S)-4-(6-{2-Fluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(R)-4-(5-Ethynyl-6-{2-fluoro-4-[2-(2-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(S)-4-(2-{2-Fluoro-4-[2-(2-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-methyl-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-Fluoro-6-(2-morpholin-4-yl-ethyl)-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[4-fluoro-6-(2-methanesulfonyl-ethyl)-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2,5-Difluoro-4-(2-isopropoxy-ethyl)-phenoxy]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-propionylsulfamoyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-sulfamoyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-sulfamoyl-ethyl)-phenoxy]-5-ethynyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-[1,2,4]triazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,3-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-{2-Fluoro-4-[2-(6-methoxy-pyridin-2-yl)-ethyl]-phenoxy}-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(3-methoxy-pyridin-2-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Fluoro-1-oxy-pyridin-4-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5′-Methoxy-6-methyl-[2,2′]bipyridinyl-5-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[2-fluoro-4-(4-methoxy-pyridin-2-yl)-phenoxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(3-methoxy-pyridin-2-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2,5-Difluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester; and4-(6-{2,5-Difluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-ethynyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester; or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 61. The compound according to claim 1 wherein saidcompound is selected from the group consisting of:4-[6-(2-Fluoro-4-morpholin-4-yl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-methanone;(6-Amino-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[5-Ethyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(2-methyl-6-pentyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-fluoro-phenyl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(2-pyridin-3-yl-ethyl)-piperidin-4-yloxy]-pyrimidine;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;4-{6-[6-(2-Methoxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine;4-(6-{2-Fluoro-4-[(2-hydroxy-ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Iodo-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[N-(2-isopropoxy-ethyl)-carbamimidoyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carboxy-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(4-Bromo-2-fluoro-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine;4-[6-(5-Methanesulfonyl-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyclopropyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-butyricacid;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanone;4-{6-[6-(2-Methoxy-ethylsulfanyl)-2-methyl-pyrid-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-(2,5-Dimethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;4-[6-(6-Chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-fluoro-phenyl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethyl-phenyl)-ethanone;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-3-yl-ethanone;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-2-one;4-(6-{2-Fluoro-4-[(2-isopropoxy-ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-methanesulfonyl-phenyl)-ethanone;1-(4-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetyl)-benzonitrile;1-(3,4-Difluoro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-1-one;4-[6-(2,4-Difluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-hexan-1-one;4-{6-[2-Fluoro-4-(2-methoxy-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(methoxy-methyl-carbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-1-one;4-[6-(4-Cyano-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-(5-Aminomethyl-4,5-dihydro-oxazol-2-yl)-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(3-Methanesulfonyl-pyrrolidin-1-yl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Benzylamino-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylamino)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(6-{6-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-hydroxycarbamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(4-isopropyl-piperazine-1-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-morpholin-4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-hydroxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carboxymethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Dimethylcarbamoylmethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-sulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-propionylsulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-phosphonooxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Bromo-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(2-methanesulfonyl-pyrimidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoylmethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-{[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-methyl}-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-3-sulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;C-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-C-(4-fluoro-phenyl)-methyleneamine;3-tert-Butoxy-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-propan-1-one;2-Ethoxy-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-(tetrahydro-furan-2-yl)-methanone;(S)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one;4-(6-{2-Fluoro-4-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-morpholin-4-yl-2-oxo-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-imidazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;(R)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one;(S)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-hydroxy-butan-1-one;(R)—N-(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-acetamide;(S)—N-(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-acetamide;(R)—N-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide;(S)—N-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid (S)-tetrahydro-furan-3-yl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid (R)-tetrahydro-furan-3-yl ester;4-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-carbamicacid tert-butyl ester;4-{6-[2-Fluoro-4-(6-methoxy-pyridin-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;3-Amino-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-1-one;2-Amino-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;4-{6-[2-Fluoro-4-(2-isopropoxy-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-[5-Methyl-6-(4-sulfo-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 62. The compound according to claim 1 wherein saidcompound is selected from the group consisting of:4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester; and4-({Cyclopropylmethyl-4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester; or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 63. The compound according to claim 1 of the formula:4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid isopropyl ester; or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 64. A pharmaceutical composition comprising at leastone compound according to claim 1 and a pharmaceutically acceptablecarrier.
 65. A method for treatment of a metabolic-related disorder inan individual comprising administering to said individual in need ofsuch treatment a therapeutically effective amount of a compoundaccording to claim
 1. 66. The method according to claim 65 wherein saidmetabolic-related disorder is selected from the group consisting of typeI diabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia and syndrome X.
 67. The methodaccording to claim 66 wherein said metabolic-related disorder is type IIdiabetes.
 68. The method according to claim 66 wherein saidmetabolic-related disorder is hyperglycemia.
 69. The method according toclaim 66 wherein said metabolic-related disorder is hyperlipidemia. 70.The method according to claim 66 wherein said metabolic-related disorderis hypertriglyceridemia.
 71. The method according to claim 66 whereinsaid metabolic-related disorder is type I diabetes.
 72. The methodaccording to claim 66 wherein said metabolic-related disorder isdyslipidemia.
 73. The method according to claim 66 wherein saidmetabolic-related disorder is syndrome X.
 74. The method according toclaim 65 wherein said individual is a mammal.
 75. The method accordingto claim 74 wherein said mammal is a human.
 76. A method of decreasingfood intake of an individual comprising administering to said individualin need thereof a therapeutically effective amount of a compoundaccording to claim
 1. 77. A method of inducing satiety in an individualcomprising administering to said individual in need thereof atherapeutically effective amount of a compound according to claim
 1. 78.A method of controlling or decreasing weight gain of an individualcomprising administering to said individual in need thereof atherapeutically effective amount of a compound according to claim
 1. 79.The method according to claim 78 wherein said individual is a mammal.80. The method according to claim 79 wherein said mammal is a human. 81.The method according to claim 80 wherein said human has a body massindex of about 18.5 to about
 45. 82. The method according to claim 80wherein said human has a body mass index of about 25 to about
 45. 83.The method according to claim 80 wherein said human has a body massindex of about 30 to about
 45. 84. The method according to claim 80wherein said human has a body mass index of about 35 to about
 45. 85. Amethod of modulating a RUP3 receptor in an individual comprisingcontacting the receptor with a compound according to claim
 1. 86. Themethod of modulating the RITP3 receptor according to claim 85 whereinsaid compound is an agonist.
 87. The method of modulating the RUP3receptor according to claim 85 wherein said modulation of the RUP3receptor is treatment of a metabolic-related disorder.
 88. The method ofmodulating the RUP3 receptor according to claim 87 wherein saidmetabolic-related disorder is selected from the group consisting of typeI diabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X.
 89. The method ofmodulating the RUP3 receptor according to claim 88 wherein saidmetabolic-related disorder is type II diabetes.
 90. The method ofmodulating the RUP3 receptor according to claim 88 wherein saidmetabolic-related disorder is insulin resistance.
 91. The method ofmodulating the RUP3 receptor according to claim 88 wherein saidmetabolic-related disorder is hyperglycemia.
 92. The method ofmodulating the RUP3 receptor according to claim 88 wherein saidmetabolic-related disorder is hyperlipidemia.
 93. The method ofmodulating the RUP3 receptor according to claim 88 wherein saidmetabolic-related disorder is hypertriglyceridemia.
 94. The method ofmodulating the RUP3 receptor according to claim 88 wherein saidmetabolic-related disorder is type I diabetes.
 95. The method ofmodulating the RUP3 receptor according to claim 88 wherein saidmetabolic-related disorder is dyslipidemia.
 96. The method of modulatingthe RUP3 receptor according to claim 88 wherein said metabolic-relateddisorder is syndrome X.
 97. The method of modulating the RUP3 receptoraccording to claim 85 wherein said individual is a mammal.
 98. Themethod of modulating the RUP3 receptor according to claim 97 whereinsaid mammal is a human.
 99. The method of modulating the RUP3 receptoraccording to claim 85 wherein said modulation of the RUP3 receptorreduces food intake of said individual.
 100. The method of modulatingthe RUP3 receptor according to claim 85 wherein said modulation of theRUP3 receptor induces satiety in said individual.
 101. The method ofmodulating the RUP3 receptor according to claim 85 wherein saidmodulation of the RUP3 receptor controls or reduces weight gain of saidindividual.
 102. The method of modulating the RUP3 receptor according toclaim 85 wherein said individual is a mammal.
 103. The method ofmodulating the RUP3 receptor according to claim 102 wherein said mammalis a human.
 104. The method according to claim 103 wherein said humanhas a body mass index of about 18.5 to about
 45. 105. The methodaccording to claim 103 wherein said human has a body mass index of about25 to about
 45. 106. The method according to claim 103 wherein saidhuman has a body mass index of about 30 to about
 45. 107. The methodaccording to claim 103 wherein said human has a body mass index of about35 to about
 45. 108. A method of producing a pharmaceutical compositioncomprising admixing at least one compound of claim 1 and apharmaceutically acceptable carrier.